
==== Front
MedComm (2020)
MedComm (2020)
10.1002/(ISSN)2688-2663
MCO2
MedComm
2688-2663
John Wiley and Sons Inc. Hoboken

10.1002/mco2.744
MCO2744
Review
Review
Pulmonary fibrosis: pathogenesis and therapeutic strategies
WANG et al.
Wang Jianhai https://orcid.org/0009-0002-2210-9667
1 2 3 4 #
Li Kuan 1 2 4 #
Hao De 1 #
Li Xue 1 2 4
Zhu Yu 5 6 zhuyutj@tmu.edu.cn

Yu Hongzhi 4 13512205663@163.com

Chen Huaiyong 1 2 3 4 huaiyong_chen@tju.edu.cn

1 Department of Respiratory Medicine Haihe Hospital Tianjin University Tianjin China
2 Department of Tuberculosis Haihe Hospital Tianjin University Tianjin China
3 Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine Tianjin Institute of Respiratory Diseases Tianjin China
4 Tianjin Key Laboratory of Lung Regenerative Medicine, Haihe Hospital Tianjin University Tianjin China
5 Department of Clinical Laboratory Nankai University Affiliated Third Central Hospital Tianjin China
6 Department of Clinical Laboratory The Third Central Hospital of Tianjin Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases Artificial Cell Engineering Technology Research Center of Tianjin Tianjin Institute of Hepatobiliary Disease Tianjin China
* Correspondence
Huaiyong Chen, Department of Respiratory Medicine, Haihe Hospital, Tianjin University, Tianjin, China.
Email: huaiyong_chen@tju.edu.cn
Hongzhi Yu, Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin University, Tianjin, China.
Email: 13512205663@163.com
Yu Zhu, Department of Clinical Laboratory, Nankai University Affiliated Third Central Hospital, Tianjin, China.
Email: zhuyutj@tmu.edu.cn

# Jianhai Wang, Kuan Li, and De Hao contributed equally to this work.

23 9 2024
10 2024
5 10 10.1002/mco2.v5.10 e74431 8 2024
18 2 2024
02 9 2024
© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Abstract

Pulmonary fibrosis (PF) is a chronic and progressive lung disease characterized by extensive alterations of cellular fate and function and excessive accumulation of extracellular matrix, leading to lung tissue scarring and impaired respiratory function. Although our understanding of its pathogenesis has increased, effective treatments remain scarce, and fibrotic progression is a major cause of mortality. Recent research has identified various etiological factors, including genetic predispositions, environmental exposures, and lifestyle factors, which contribute to the onset and progression of PF. Nonetheless, the precise mechanisms by which these factors interact to drive fibrosis are not yet fully elucidated. This review thoroughly examines the diverse etiological factors, cellular and molecular mechanisms, and key signaling pathways involved in PF, such as TGF‐β, WNT/β‐catenin, and PI3K/Akt/mTOR. It also discusses current therapeutic strategies, including antifibrotic agents like pirfenidone and nintedanib, and explores emerging treatments targeting fibrosis and cellular senescence. Emphasizing the need for omni‐target approaches to overcome the limitations of current therapies, this review integrates recent findings to enhance our understanding of PF and contribute to the development of more effective prevention and management strategies, ultimately improving patient outcomes.

This figure illustrates the interconnected and mutually reinforcing relationship between the study of mechanisms, diagnosis, and treatment of PF. The cycle begins with understanding the mechanisms underlying PF, which leads to the formulation of novel hypotheses. These hypotheses drive the development of new diagnostic tools and classification efforts, enhancing the ability to accurately identify and treat the disease. Insights gained from diagnostics inform therapeutic strategies, leading to novel interventions that improve patient outcomes. As new therapies are implemented, they provide feedback that refines our understanding of mechanisms and diagnostics, thus perpetuating the cycle of innovation and improvement. Throughout this process, various omics technologies are utilized to explore and elucidate the complexities of PF, ensuring a comprehensive and detailed approach to its study and management

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biomarkers
endothelium
epithelium
immune cells
microbiome
National Natural Science Foundation of China 10.13039/501100001809 82100077 82070001 82400091 Tianjin second batch of health industry high‐level talent selection and training projectTJSQNYXXR‐D2‐070 TJSJMYXYC‐D2‐012 Natural Science Foundation of Tianjin 10.13039/501100006606 21JCZDJC00430 21JCQNJC00550 23JCYBJC01560 Tianjin Science and Technology Plan Project22JCYBJC00730 Science and Technology Planning Project of Tianjin Municipal Education Commission2022YGYB14 Tianjin Key Medical Discipline (Specialty) Construction ProjectTJYXZDXK‐067C source-schema-version-number2.0
cover-dateOctober 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:23.09.2024
Wang J , Li K , Hao D , et al. Pulmonary fibrosis: pathogenesis and therapeutic strategies. MedComm. 2024;5 :e744. 10.1002/mco2.744
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pmc1 INTRODUCTION

Pulmonary fibrosis (PF) is a chronic, progressive lung disease marked by excessive accumulation of extracellular matrix (ECM) components, resulting in lung tissue scarring and impaired respiratory function. 1 Idiopathic pulmonary fibrosis (IPF) is the most common form of PF, with its prevalence rising globally in recent years. The annual incidence of IPF is estimated to be 0.57–4.51 cases per 100,000 in Asia, 0.33–2.51 cases in Europe, and 2.4–2.98 cases in North America. 2 IPF is more frequent in males and uncommon in individuals under 50, with a median diagnosis age of approximately 65 years. 3 The disease course is unpredictable, with a poor prognosis and an average survival of 2−3 years. Acute exacerbations may occur, significantly increasing mortality. 4

Despite extensive research, several gaps remain in the understanding of PF. The exact mechanisms by which genetic predisposition and environmental exposure synergize to initiate and propagate fibrotic processes have not yet been fully elucidated. The role of immune responses, particularly the contribution of different immune cell subsets, in modulating fibrosis requires further investigation. Current therapeutic strategies for PF primarily focus on the use of anti‐inflammatory and antifibrotic agents. Although these treatments can slow disease progression, they do not reverse established fibrosis and are often associated with significant side effects. Therefore, innovative therapies that target the underlying mechanisms of PF and offer better efficacy and safety profiles are urgently needed.

Recent studies have identified several key factors that contribute to the development of PF. Occupational and environmental exposures, including the inhalation of harmful substances such as asbestos, silica dust, and organic antigens, are significant contributors. These agents directly injure the lung tissue, triggering chronic inflammation and fibrotic processes. 5 Additionally, lifestyle factors, such as smoking and chronic alcohol consumption, are strongly correlated with an increased risk of PF. 6 Smoking introduces toxic constituents into the lungs, causing oxidative stress and inflammation that promote fibrotic changes. Chronic alcohol consumption impairs the natural repair mechanisms of the lungs, predisposing individuals to fibrosis. 6 Preexisting medical conditions such as gastroesophageal reflux disease (GERD) and chronic viral infections also play critical roles in the pathogenesis of PF by perpetuating chronic inflammation and lung tissue damage. 7 , 8

The pathogenesis of PF involves a complex interplay of various cellular and molecular mechanisms. At the cellular level, interactions among epithelial cells, fibroblasts, immune cells, and endothelial cells (ECs) are crucial for driving the fibrotic process. 9 Alveolar epithelial cells, particularly type II alveolar cells (AT2), play a significant role in lung repair and regeneration. 10 However, repeated injury to these cells can lead to aberrant repair mechanisms, resulting in the differentiation of fibroblasts into myofibroblasts, which are central to the fibrotic response. 11 , 12 These myofibroblasts produce excessive ECM components, leading to scarring and stiffening of lung tissue. The molecular pathways implicated in PF include the TGF‐β/Smad, WNT/β‐catenin, and PI3K/Akt/mTOR signaling pathways. These pathways regulate various aspects of cell proliferation, differentiation, and apoptosis and contribute to the progression of fibrosis.

This review first examines the etiological and risk factors associated with PF, including genetic and environmental influences. It then explores the cellular and molecular mechanisms underlying the disease, with an emphasis on key signaling pathways. Subsequently, the review assesses current diagnostic tools, biomarkers, and therapeutic strategies, including emerging treatments. Finally, it discusses future research directions, highlighting the need for innovative, multitargeted approaches for effective disease management. By integrating the latest research and identifying critical gaps, this review aims to connect academic research with clinical practice, advancing the understanding and treatment of PF.

2 PATHOGENESIS OF PF

The etiology of PF involves a complex interplay between genetic factors, environmental exposure, and underlying medical conditions (Figure 1). A comprehensive understanding of these risk factors is crucial to develop targeted prevention and management strategies for this debilitating disease. This section discusses the multifaceted etiological factors, cellular and molecular mechanisms, inflammatory and fibrotic processes, and roles of various cell types involved in PF.

FIGURE 1 PF risk factors. This diagram illustrates the multifactorial risk factors associated with PF, categorized into four main groups: demographic/clinical, occupational and environmental exposures, genetic factors, and lifestyle factors. This figure was designed using BioRender (https://biorender.com/).

2.1 Etiology and risk factors

2.1.1 Occupational and environmental exposures

Occupational and environmental exposures are significant contributors to PF. Inhalation of harmful substances such as asbestos, silica dust, and organic antigens can trigger chronic lung inflammation and fibrosis. 13 , 14 These agents directly injure the lung tissue, initiating a persistent inflammatory response. For example, workers in construction and mining are at higher risk because of their exposure to silica dust, which can lead to silicosis and subsequent PF. 15 Similarly, exposure to asbestos, which is commonly found in older buildings, can cause asbestosis, a condition strongly associated with PF. 16 Additionally, certain agricultural exposures, such as the inhalation of moldy hay (farmer's lungs) or bird droppings (bird fancier's lungs), can lead to hypersensitivity pneumonitis, which may progress to PF if not properly managed. 17 Environmental pollutants such as traffic‐related air pollution have also been implicated in the development of PF. 18 , 19 , 20 These pollutants induce oxidative stress and inflammation, contributing to lung tissue damage and fibrosis.

2.1.2 Lifestyle factors

Lifestyle factors significantly influence the risk of PF. Smoking is a major risk factor for PF, and studies have shown a strong correlation between cigarette smoke exposure and PF development. 21 , 22 The toxic constituents of cigarette smoke, including reactive oxygen species (ROS) and proinflammatory agents, cause direct lung tissue damage and induce chronic inflammatory processes. Inflammation and tissue damage create a favorable environment for fibrosis. 23 Chronic alcohol consumption has also been linked to PF. 24 Alcohol impairs the natural repair mechanisms of the lungs, making them more susceptible to fibrosis. Alcohol‐induced oxidative stress and inflammation are thought to play important roles in this process. 25 Additionally, lifestyle factors such as poor diet and lack of physical activity, which contribute to poor overall health, can exacerbate the risk of developing PF.

2.1.3 Demographic factors and comorbidities

Demographic and clinical factors are associated with an increased risk of PF. Age is a significant risk factor, with PF most commonly diagnosed in individuals aged 50−70 years. 26 Additionally, sex plays a role as IPF, the most common type, is more prevalent in men than in women. 27 , 28 GERD is a notable example. It can lead to the microaspiration of stomach contents into the lungs, causing chronic irritation and inflammation, which can result in fibrotic changes over time. Chronic inflammation due to microaspiration is thought to damage the lung epithelium and promote fibrosis. 29 Moreover, chronic viral infections have been implicated in PF pathogenesis. 30 , 31 Hepatitis C and Epstein–Barr virus infections are notable examples. These viruses can persist in the body and cause chronic immune activation and inflammation, contributing to lung tissue damage and fibrosis. 32 , 33 Additionally, other chronic infections and autoimmune diseases, such as rheumatoid arthritis and systemic sclerosis, are associated with a higher incidence of PF, suggesting a link between chronic systemic inflammation and lung fibrosis. 34

2.1.4 Genetic susceptibility

Genetic susceptibility to idiopathic IPF has been increasingly elucidated through genome‐wide association studies (GWAS) and whole‐exome sequencing. The MUC5B promoter polymorphism (rs35705950) is highly prevalent among patients with IPF and is significantly associated with disease development by altering mucin production, potentially leading to aberrant epithelial repair and fibrosis. 35 , 36 Telomere‐related genes such as TERT, TERC, and RTEL1 are also critical, with variants linked to both familial and sporadic forms of PF through telomere shortening and chromosomal instability. 37 , 38 , 39 Mutations in surfactant protein genes, such as SFTPC and SFTPA2, disrupt surfactant metabolism, leading to increased lung injury and fibrosis. 40 , 41 , 42 , 43 GWAS have identified additional susceptibility loci, including TOLLIP and DSP, that affect the immune response and cell adhesion pathways. 44 , 45 , 46 Other implicated genes include HLA, AKAP13, SPPL2C, and KIF15, highlighting their roles in immune regulation, profibrotic signaling, and mitotic spindle assembly in IPF. 47 , 48 , 49 , 50

Familial aggregation significantly affects the progression and prognosis of IPF, with familial cases often presenting earlier and more aggressively than sporadic cases. 51 Genetic predisposition, particularly involving telomere‐related genes, complicates treatment strategies because of varying responses to conventional therapies. 52 , 53 , 54 Genetic screening and counseling are essential for early diagnosis and personalized treatment to improve disease management and outcomes.

2.2 Fibrotic progression

The etiology of PF remains elusive; however, significant advancements have been made in understanding the underlying mechanisms of this chronic lung disease. Current knowledge indicates that PF arises from progressive dysfunction due to abnormal repair mechanisms triggered by repetitive injury to alveolar epithelial cells. 12 , 55 These microinjuries primarily affect AT2 cells and provoke immune or inflammatory responses in lung immune cells, exacerbating damage to both epithelial and ECs. 56 This cascade of events leads to the reprogramming of affected epithelial cells, causing them to secrete numerous profibrotic factors and become abnormally activated. This process compromises the epithelial integrity and activates aberrant repair mechanisms and stress response pathways, culminating in the differentiation of fibroblasts into myofibroblasts. 11

The pathogenesis of PF can be conceptualized into three main stages: immune and inflammatory responses in the alveoli, alveolar repair, and fibrosis. The cumulative effects of these stages, including inflammation, tissue damage, and repair, ultimately lead to fibrotic changes. 57 Environmental factors such as dust and other harmful substances contribute to this process by causing injury to alveolar epithelial cells and capillary ECs. This injury disrupts the basement membrane, leading to the abnormal proliferation of AT2 and ECs. This results in the failure of re‐epithelialization and re‐endothelialization of the alveolar–capillary barrier, collapse of the alveoli, formation of fibrous clots, proliferation of fibroblasts, and transformation of fibroblasts into myofibroblasts. 58

Moreover, damaged lung epithelium loses its ability to regulate fibroblast proliferation and matrix deposition, leading to excessive ECM accumulation and PF development. 59 The intricate interplay between these cellular responses underscores the complexity of PF pathogenesis, in which immune responses, environmental factors, and abnormal cellular repair mechanisms converge to drive fibrotic processes.

2.3 Cellular contributions to PF

The pathogenesis of PF involves a complex interplay between various cell types and the microbiome. This section highlights the roles of mesenchymal, epithelial, immune, and ECs and the microbiome in PF (Figure 2).

FIGURE 2 Cellular and microbiome contributions to PF. This schematic illustrates the various cell types and microbiome components involved in the pathogenesis of PF, highlighting their roles and interactions within the lung microenvironment. This figure was designed using BioRender (https://biorender.com/).

2.3.1 Lung fibroblasts

In PF, lung fibroblasts produce significant amounts of collagen, crucial for disease progression. Key cell types include fibroblasts, myofibroblasts, and lipofibroblasts. Advances in single‐cell sequencing have revealed that multiple mesenchymal cell subtypes have distinct gene expression profiles and functions.

Fibroblasts, which are derived from embryonic mesenchymal cells, are distributed throughout the body and are essential for tissue repair and local cellular response regulation. Fibroblast activation in the lungs involves cell proliferation, migration, and ECM production. 60 This activation is significant in PF, in which ECM deposition is a fundamental pathological feature. Since the mid‐1990s, several studies have highlighted the role of alveolar fibroblasts in alveolar epithelial proliferation and differentiation. 61 Alveolar fibroblasts provide and modify ECM scaffolds, generate tensile forces for septal wall extension, and deliver paracrine signals essential for cellular proliferation and differentiation. 61 During PF, fibroblasts are activated by cytokines, growth factors, and mechanical stress, leading to their differentiation into myofibroblasts. The continuous activation and proliferation of myofibroblasts contribute to PF progression. 62 Notably, inhibition of fibroblast differentiation can improve fibrosis. For instance, TGF‐β induces high MBD2 expression, promoting fibroblast differentiation into myofibroblasts and leading to PF. 63 Fibroblasts from patients with IPF are notably more invasive and potentially driven by HER2 signaling, which enhances fibroblast invasiveness and worsens PF. 64

Myofibroblasts were first identified in rat wound granulation tissue and exhibited characteristics of both fibroblasts and smooth muscle cells. 65 They play an essential role in rapid tissue repair by depositing collagen scars. 62 In PF, myofibroblasts originate from resident fibroblasts, epithelial‐to‐mesenchymal transition (EndMT), and circulating fibrocytes, leading to excessive fibrosis and impaired lung function. 66 , 67 The inhibition of myofibroblast function can reduce fibrosis. 68 , 69

Lipofibroblasts, which were first identified in rat lungs, contain substantial lipid bodies and are located near AT2 cells. 70 Their presence in human lungs remains controversial. Lipofibroblasts store and synthesize vitamin A, contribute to surfactant production, and play a vital role in alveolar development. Recent research suggests that transforming lipofibroblasts into myofibroblasts contributes to the pathogenesis of experimental lung fibrosis and the reversal of ECM deposition, highlighting fibroblast phenotype modification as a therapeutic approach. 71 During lung fibrosis, lipofibroblasts transform into myofibroblasts through TGF‐β1 signaling. These activated myofibroblasts accumulate in fibrotic regions, producing large amounts of ECM proteins, particularly collagen, leading to the destruction of the lung architecture and impaired gas exchange. Some myofibroblasts can dedifferentiate back into a lipofibroblast‐like phenotype during fibrosis resolution, regulated by PPARγ signaling. 72 Promoting adipogenic differentiation of myofibroblasts can combat persistent PF, as demonstrated by omentin‐1′s ability to reverse established PF. 73

Advancements in single‐cell sequencing have revealed several new fibroblast subtypes, each of which has a distinct role in PF. Xie et al. 74 identified three subtypes: Col13a1 matrix fibroblasts, Col14a1 matrix fibroblasts, and mesenchymal progenitors. The proportion of matrix fibroblasts in fibrotic mesenchymal cells increased from 30 to 50%. Mesenchymal progenitors differentiate into lipofibroblasts and Col14a1 matrix fibroblasts. Additionally, PDGFRBhigh fibroblasts, which are significantly increased in fibrotic lungs, contribute to ECM production by upregulating ECM‐related genes and differentiating into Col13a1 and Col14a1 matrix fibroblasts. Liu et al. 75 identified a novel mesenchymal subpopulation characterized by Ebf1, which has a unique transcriptomic signature. In the embryonic lungs, this population coexpresses pericyte markers. In adult and fibrotic lungs, Ebf1+ populations diverge into groups with pericyte markers or unique signatures. A similar mesenchymal population has been identified in the human postnatal lung, along with a distinct pericyte cluster. Lee et al. 75 identified that p16INK4a+ fibroblasts play a role in the formation of pathological fibroblast subsets in IPF.

2.3.2 Epithelial cells

There are various types of lung epithelial cells, including AT2, alveolar type 1 (AT1), club, and basal cells, each playing distinct roles in lung function and contributing differently to fibrosis.

The alveolar epithelium, which is essential for gas exchange, comprises AT1 and AT2 cells. AT1 cells cover approximately 96% of the alveolar surface area, but are fewer in number owing to their large, flattened shape, which facilitates efficient gas exchange. 10 In contrast, AT2 cells cover only 4% of the surface but constitute 60% of alveolar epithelial cells, producing pulmonary surfactants that reduce surface tension and prevent lung collapse. 76 , 77 AT2 cells also act as progenitor cells that are crucial for alveolar repair and regeneration. 10 , 78 Upon injury, AT2 cells differentiate into AT1 and new AT2 cells, aiding epithelial restoration. 79 , 80 AT2 cell dysfunction is the key driver in PF. Senescence rather than the loss of these cells leads to fibrosis, with p53 activation playing a significant role. 56 Damaged AT1 cells prompt AT2 cells to differentiate, a process involving transitional cells such as prealveolar type 1 transitional state cells, which are prone to DNA damage and show enriched TP53 and TGFβ signaling. 81 Damage‐associated transitional progenitors also differentiate into AT1 cells after lung injury, with similar cells found in IPF tissue samples. 82

Club cells, which are nonciliated bronchiolar epithelial cells, are involved in xenobiotic metabolism, immune regulation via club cell secretory proteins, and progenitor cell activity, which is essential for epithelial repair. 82 , 83 Club cells play a significant role in IPF pathogenesis. 84 , 85 In IPF, club cells undergo phenoconversion, losing their typical morphology and acquiring the properties of alveolar epithelial cells, including the upregulation of proteins such as Claudin 10. 84 , 85 This phenomenon is associated with the initiation and progression of IPF, as phenoconverted club cells exhibit pleomorphism, migrate to alveolar regions, and contribute to alveolar bronchiolization and fibroblastic foci development. 84 , 86 Additionally, club cells activate fibroblasts paracrinally by secreting factors such as TGF‐β, playing a crucial role in fibrosis. Knockout models have demonstrated that ablation of key genes such as PDCD5 in club cells significantly reduces fibrotic marker expression and fibrosis development. 87

Basal cells, known as KRT5+ epithelial progenitors, are essential for maintaining and repairing the pseudostratified epithelium of the respiratory tract. 88 They respond to epithelial injury by differentiating into various specialized cell types, such as ciliated and secretory cells, and by maintaining a reservoir of progenitor cells. 89 , 90 In IPF, basal cells undergo notable changes, including hyperplasia and honeycomb cyst formation, which are characteristic of advanced IPF. 91 Single‐cell RNA sequencing (scRNA‐seq) has revealed distinct basal cell subtypes in healthy and fibrotic lungs, highlighting their heterogeneity and dynamic responses to fibrotic cues. 92 , 93 , 94 In normal lungs, basal cells include multipotent progenitors and secretory‐primed basal cells (SPBs), the latter of which show similarities to basal cells in fibrotic tissues. 95 This shift toward a secretory‐primed state is linked to mucociliary dysfunction and mucus overproduction in IPF. 96 SPBs are abundant in regions expressing MUC5B within honeycomb cysts, connecting basal cell plasticity to the pathogenesis of fibrosis. 93 Basal cells in IPF show increased expression of markers such as KRT14, VIM, and MMP7, indicating a transition to a mesenchymal‐like phenotype that contributes to fibrotic remodeling. 86

2.3.3 Immune cells

Immune response is a significant driver of fibrosis. The initial injury to AT2 cells triggers the release of various danger signals and cytokines, such as IL‐1β, TNF‐α, and IL‐6, which attract and activate immune cells. These immune cells, including macrophages, neutrophils, and lymphocytes, migrate to the site of injury and release additional proinflammatory mediators. This inflammatory milieu is essential for initiating tissue repair but can become chronic and pathological if unresolved.

Macrophages play a crucial role in the pathogenesis and progression of fibrotic lung disease through various mechanisms involving different subtypes and secretory profiles. Alveolar macrophages (AMs), interstitial macrophages (IMs), and monocyte‐derived macrophages are the primary populations involved in fibrotic processes. 97 , 98 AMs, typically maintaining lung homeostasis, become profibrotic under pathological conditions by producing TGF‐β, PDGF, FGF, and VEGF, which stimulate fibroblast proliferation and collagen synthesis. IMs contribute to fibrogenesis through interactions with structural cells and the secretion of profibrotic mediators such as CCL18. 99 Subsets of IMs, such as Lyve1hiMHCIIlo IMs, aid in leukocyte chemotaxis and wound healing, whereas Lyve1loMHCIIhi IMs are involved in antigen presentation and T cell activation. 100 Monocyte‐derived macrophages infiltrate the lungs post‐injury and differentiate into profibrotic macrophages with high expression of fibrogenic genes such as PDGFA and CSF1, whose inhibition suppresses fibrosis. 101 , 102 Single‐cell transcriptomics have identified distinct macrophage populations in fibrotic lungs, including those expressing high levels of SPP1 and CHI3L1. 103 The plasticity of macrophages allows them to adopt different phenotypes; in fibrosis, the M2‐like phenotype predominates, characterized by IL‐10 and TGF‐β secretion, promoting tissue repair and ECM production. 104 Macrophages also regulate ECM synthesis and degradation through MMPs and their inhibitors, with the roles varying according to the MMP type. 97 Novel subsets, such as SatMs, specifically exacerbate fibrosis. 105 Understanding these roles will offer potential therapeutic avenues for mitigating fibrosis and improving patient outcomes.

Neutrophils are abundant in the lungs and bronchoalveolar lavage fluid (BALF) of patients with IPF and correlate with disease severity and poor prognosis. Elevated levels of neutrophil‐associated chemokines and proteins, such as interleukin‐8 (IL‐8) and S100A9, underscore the significant role of neutrophil‐driven inflammation in IPF. 106 Neutrophils contribute to lung fibrosis by releasing neutrophil extracellular traps (NETs), which exacerbate tissue damage and promote fibrotic pathways while trapping and killing pathogens. NETs induce fibroblast differentiation into myofibroblasts, which are essential for collagen deposition and tissue remodeling, mediated by proteins such as neutrophil elastase (NE) and myeloperoxidase, which are found at elevated levels in patients with IPF. 107 In mouse models of PF, the depletion of neutrophils or inhibition of their recruitment significantly reduce fibrosis. Mice lacking NE or those treated with NE inhibitors are protected from bleomycin‐induced fibrosis, a common IPF model. Additionally, the inhibition of formyl peptide receptor 1, which is crucial for neutrophil chemotaxis, mitigates fibrosis by reducing neutrophil infiltration. 108 Neutrophils also secrete MMPs, which degrade ECM components and facilitate tissue remodeling, contributing to the aberrant repair and perpetuation of fibrosis in IPF. 109 Moreover, neutrophils interact with other immune cells and fibroblasts to enhance fibrotic responses. Neutrophil‐derived leukotrienes promote the recruitment of additional inflammatory cells, amplifying the inflammatory and fibrotic cascade and underscoring the complexity of their role in IPF pathogenesis.

Lymphocytes play a multifaceted role in the pathogenesis of PF by engaging in both protective and pathological processes in the pulmonary microenvironment. In PF, the immune microenvironment is significantly altered, with elevated frequencies of memory B cells, plasma cells, and activated memory CD4+ T cells compared with those in healthy lungs, suggesting an enhanced adaptive immune response that may contribute to disease progression. 110 T helper 2 cytokines, such as IL‐4, IL‐5, IL‐9, and IL‐13, produced by CD4+ T cells promote fibrosis by enhancing fibroblast activity and collagen deposition. Conversely, T regulatory cells (Tregs) and Th1 cells may exert antifibrotic effects through cytokines such as interferon‐gamma (IFN‐γ) and IL‐10. 111 , 112 B cells also contribute to fibrosis, with lymphoid aggregates composed of T, B, and dendritic cells present in IPF lungs, indicating a role for adaptive immune responses in fibrosis. B cells can differentiate into plasma cells that produce autoantibodies, potentially exacerbating tissue damage and fibrosis. 113 Plasma cells and their antibodies are increasingly found in fibrotic lungs, indicating an ongoing immune response to self‐antigens or persistent infections. 114 CD8+ T cells in IPF lungs show signs of activation and proliferation driven by chronic antigen exposure and inflammatory signals, contributing to tissue damage through cytotoxic activity and profibrotic cytokines such as TGF‐β. 115 , 116 The involvement of Tregs in IPF is complex, as they may either mitigate or exacerbate fibrosis depending on the context of their activation and cytokine production. 117 The interplay between lymphocyte subsets and secreted factors underscores the complexity of immune regulation in patients with IPF. Targeting specific lymphocyte functions and associated signaling pathways may offer new therapeutic avenues for managing IPF, highlighting the need for a nuanced understanding of the role of immune cells in this chronic lung disease.

Group 2 innate lymphoid cells (ILC2s) contribute significantly to the pathogenesis of IPF. Activated by cytokines such as IL‐33, IL‐25, and TSLP, ILC2s produce type 2 cytokines, including IL‐5 and IL‐13, which are critical for the development of fibrosis. 118 Studies in Regnase‐1‐deficient mice have shown that the absence of this post‐transcriptional regulator leads to ILC2 proliferation and activation, resulting in enhanced fibrosis. This is because Regnase‐1 normally degrades mRNAs encoding fibrosis‐related cytokines and transcription factors such as Gata3 and Egr1. 119 In IPF, reduced IFN‐γ signaling leads to spontaneous ILC2 activation, promoting fibrosis. In Ifngr1−/−Rag2−/− mice, the progression of fibrosis depends on IL‐33, with activated ILC2s inducing collagen production in fibroblasts, highlighting their direct role in fibrosis. 120 Human studies have also shown that increased ILC2s in the peripheral blood and BALF correlate with disease severity and poor prognosis in patients with IPF, indicating a role similar to that in mouse models. Further research has shown that ILC2s, when activated by IL‐33, upregulate fibrosis‐associated genes and directly stimulate collagen production from fibroblasts. Coculture systems demonstrated that activated ILC2s significantly enhanced collagen deposition in fibroblasts. 119 Depletion of ILC2s in mouse models reduces fibrosis, underscoring their essential role in the fibrotic process. 120 In summary, ILC2s play a pivotal role in PF development and progression by producing profibrotic cytokines, interacting with fibroblasts, and contributing to collagen deposition. Regulating ILC2 activity, particularly through factors like Regnase‐1 and IFN‐γ signaling, represents a potential therapeutic target for mitigating fibrosis in patients with IPF.

2.3.4 Endothelial cells

ECs play a critical role in PF pathogenesis. ECs contribute to fibrosis through EndMT, dysregulated angiocrine signaling, and interactions between fibroblasts and epithelial cells. 121 , 122 During EndMT, ECs acquire mesenchymal traits, thereby increasing the myofibroblast pool involved in ECM deposition. Yanagihara et al. 122 , 123 demonstrated that deleting matrix Gla protein in ECs activates TGF‐β signaling, promoting myofibroblast transition and worsening fibrosis. Conversely, inducing FoxA2 can reverse myofibroblasts back to ECs, suggesting its therapeutic potential in targeting EndMT. 122 , 123 EC–epithelial crosstalk is vital for lung homeostasis and repair. Chen et al. 124 showed that lung ECs secrete angiocrine factors influencing AT2‐to‐AT1 cell differentiation, which is essential for lung repair, with Flt1 (VEGFR1) as the key regulator. Flt1 knockout in ECs reproduces the antifibrotic effects of microRNA‐200c and promotes epithelial trans‐differentiation, highlighting the importance of endothelial–epithelial signaling in mitigating fibrosis. 125 Endothelial dysfunction and altered signaling pathways contribute to pulmonary vascular remodeling in PF. Loss of BMPR‐II signaling in ECs exacerbates endothelial dysfunction and promotes fibrogenesis through enhanced interactions with fibroblasts. 126 scRNA‐seq has revealed the heterogeneity of EC populations, underscoring their complex roles in PF. These findings underscore the multifaceted roles of ECs in PF, suggesting that targeted therapies addressing endothelial dysfunction and signaling pathways could offer promising avenues for mitigating the progression of this debilitating disease.

2.4 Microbiome contribution

2.4.1 Lung microbiome

The lung microbiome, which comprises diverse bacterial, viral, and fungal communities, significantly influences respiratory health and disease progression. Alterations in the lung microbiome have been observed in various lung diseases and have been shown to affect disease outcomes. The composition, diversity, and bacterial burden of the lung microbiome are crucial for maintaining homeostasis and influencing the disease state. In healthy individuals, the lung microbiome maintains a stable and diverse community structure by balancing bacterial migration, emigration, and replication. However, in lung diseases, such as PF, this balance is disrupted, leading to changes in microbial diversity and composition. 127 Reduced microbial diversity (alpha diversity) and increased bacterial burden are associated with poor clinical outcomes and disease progression. 128 Studies have found lower alpha diversity in patients with fibrotic lung conditions than in healthy controls, which is correlated with increased inflammation and lung fibrosis. 129 Higher bacterial loads in the lower airways of patients with PF are associated with worse outcomes including higher mortality. This increased burden may result from enhanced bacterial migration or reduced bacterial clearance due to impaired mucociliary function. Specific bacterial taxa such as Streptococcus and Staphylococcus are associated with increased inflammation and tissue damage, exacerbating lung injury. 130 The lung microbiome influences local immune responses, promoting either a protective or a pathogenic environment. Certain bacterial communities during fibrosis induce profibrotic immune responses, including Th17 cell activation and proinflammatory cytokine production. 127 Disruptions in microbial communities can impair host defenses, increasing the susceptibility to infections and lung damage. 127 These insights highlight the critical role of the lung microbiome in PF, suggesting that therapeutic strategies aimed at restoring the microbial balance could potentially mitigate disease progression and improve clinical outcomes.

2.4.2 Gut microbiome

The gut microbiome influences various systemic diseases, including lung conditions, through the gut–lung axis, which is a bidirectional communication network linking the gastrointestinal and respiratory systems. Alterations in gut microbiota composition or dysbiosis are associated with the progression of several lung diseases by influencing immune responses and systemic inflammation. In mouse models of PF, distinct changes in the gut microbiome contribute to disease pathogenesis and progression. Gut dysbiosis exacerbates PF by increasing intestinal permeability, allowing microbial products, such as lipopolysaccharides (LPS), to enter the bloodstream, induce systemic inflammation, and augment fibrotic processes in the lungs. 131 This systemic inflammation is mediated through Toll‐like receptor activation and the release of proinflammatory cytokines, perpetuating lung tissue remodeling and fibrosis. 131 Gut microbiota‐derived metabolites modulate lung health. Short‐chain fatty acids (SCFAs) produced by fermenting dietary fibers possess anti‐inflammatory properties and may protect against fibrosis. Conversely, the depletion of beneficial SCFA‐producing bacteria and the accumulation of harmful metabolites enhance fibrotic responses. Notably, metabolites such as trigonelline, betaine, and cytosine are altered in fibrotic conditions, correlating with disease severity. 132 Modulation of the gut microbiota through dietary interventions, probiotics, or antibiotics has shown promise in altering disease outcomes. Specific probiotics reduce lung inflammation and fibrosis in experimental models, suggesting that targeting gut dysbiosis may be a viable adjunctive strategy for managing PF. 132 Mechanistic insights from 16S rDNA sequencing and metabolomics have revealed significant alterations in the gut bacterial taxa and metabolites in fibrotic models. 133 Genera such as Alloprevotella, Helicobacter, Rikenella, and Dubosiella are correlated with fibrotic indicators, suggesting potential biomarkers for disease progression. 134 Further research is necessary to translate these findings into clinical practice and to explore gut microbiota‐targeted therapies for managing PF.

2.5 Molecular pathways

2.5.1 TGF‐β/Smad pathway

TGF‐β is a multifunctional cytokine regulating cellular processes including proliferation, differentiation, and apoptosis. 135 It plays a critical role in PF, mainly by transforming fibroblasts into myofibroblasts, which are key for ECM production. 136 The TGF‐β signaling pathway involves the phosphorylation of Smad proteins, which migrate to the nucleus to regulate genes linked to PF. 136 TGF‐β also boosts the production of connective tissue growth factor (CTGF), augmenting fibrosis via increased ECM synthesis. It also inhibits ECM degradation by regulating MMPs and tissue inhibitors of metalloproteinases, leading to ECM accumulation. 135 , 137

Experimental models highlight TGF‐β’s significance in fibrosis progression, with its overexpression in mouse lungs causing substantial fibrosis. 138 Conversely, inhibiting TGF‐β signaling mitigates fibrosis, suggesting therapeutic potential. 138 Antifibrotic treatments targeting TGF‐β signaling pathways, including neutralizing antibodies and small molecule inhibitors, have demonstrated efficacy in preclinical trials. 139 Furthermore, noncanonical TGF‐β signaling pathways involving mitogen‐activated protein kinases (MAPKs) and the phosphoinositide 3‐kinase (PI3K)/Akt pathway, along with interactions with other profibrotic mediators such as IL‐6 and angiotensin II, intensify fibrotic responses, 140 underscoring the complexity of TGF‐β’s role in PF. Clinical evidence supports TGF‐β’s pivotal involvement in PF pathogenesis, as elevated levels have been detected in the BALF and lung tissues of patients with IPF. 141 Genetic links have also been found, with polymorphisms in the TGF‐β1 gene associated with increased susceptibility to IPF. 142 Ongoing clinical trials focus on the efficacy of various TGF‐β inhibitors to reduce fibrosis and improve lung function, offering potential new therapeutic avenues that could change the course of this debilitating disease. 135

2.5.2 WNT/β‐catenin signaling

WNT signaling pathways are classified into canonical (β‐catenin‐dependent) and noncanonical (β‐catenin‐independent) pathways. In the context of PF, both pathways are implicated, although the canonical WNT/β‐catenin pathway has been more extensively studied. Activation of the canonical WNT pathway typically involves the binding of WNT ligands to Frizzled receptors and coreceptors, such as LRP5/6, leading to the stabilization and nuclear translocation of β‐catenin. 143 This, in turn, results in the transcription of WNT target genes that promote fibrotic responses. 143

Pirfenidone, an antifibrotic drug, alleviates PF by regulating the WNT/β‐catenin and TGF‐β/Smad pathways. Pirfenidone inhibits the activation of the WNT/β‐catenin pathway, which is otherwise upregulated in fibrotic lung tissues. 144 By suppressing β‐catenin signaling, pirfenidone reduces the expression of fibrotic markers such as collagen and α‐SMA, thereby mitigating ECM deposition and fibrosis progression. 144 Noncanonical WNT signaling pathways such as WNT5A and WNT11 promote myofibroblast differentiation and exacerbate fibrotic responses. This suggests that different branches of the WNT signaling network may contribute distinctively to the pathology of PF. 145 Moreover, basal cell‐derived WNT7A plays a pivotal role in promoting fibrogenesis in the fibrotic niche of IPF. 146 WNT7A signaling in the fibrotic microenvironment enhances fibroblast recruitment and activation, leading to increased collagen production and tissue stiffening. 146 This finding underscores the importance of localized WNT signaling in modulating the fibrotic niche, and suggests that targeting specific WNT ligands may offer therapeutic benefits.

2.5.3 PDGF signaling

PDGF is a homo‐ or heterodimeric molecule consisting of four different polypeptide chains (PDGF‐A, ‐B, ‐C, and ‐D) that interact with two types of PDGF receptors (PDGFR‐α and PDGFR‐β). These interactions result in receptor dimerization and autophosphorylation, activating several downstream signaling pathways, including Ras–MAPK, PI3K, and PLC‐γ, which regulate cell proliferation, migration, and survival. 147 PDGF signaling has been shown to be upregulated in PF mouse models, suggesting its critical role in the disease pathology. 148 Several studies have demonstrated the increased expression of PDGF and its receptors in fibrotic lung tissues. For instance, Zhao et al. 149 reported elevated levels of PDGF‐A in a bleomycin‐induced PF mouse model. Additionally, Walsh et al. 150 found increased PDGF‐BB and PDGF‐AA peptide levels in the BALF of rats treated with bleomycin, highlighting the role of these growth factors in promoting lung fibroblast growth. Similarly, both PDGF‐A and PDGF‐B at the mRNA and protein levels are increased in bleomycin‐treated mouse lungs. 151

2.5.4 PI3K/Akt and mTOR pathways

The PI3K/Akt pathway, upon activation by various stimuli, initiates a cascade of signaling events that promotes cell survival, proliferation, and metabolism. AKT, a central node in this pathway, phosphorylates and activates numerous downstream targets, including mTOR. The mTOR pathway, particularly mTOR complex 1 (mTORC1), is a crucial regulator of cellular growth and metabolism, influencing protein synthesis, autophagy, and lipid metabolism. 152 Notably, the PI3K/Akt/mTOR pathway is significantly upregulated in PF. 153 For example, LPS induces fibroblast proliferation and collagen synthesis through this pathway. LPS promotes aerobic glycolysis in lung fibroblasts via the PI3K/Akt/mTOR pathway, leading to increased collagen production. This metabolic shift, often referred to as the Warburg effect, supports the energetic and biosynthetic demands of proliferating fibroblasts and myofibroblasts in fibrotic tissues. 153 Inhibitors targeting the PI3K/Akt/mTOR pathway have shown promise in preclinical PF models. For example, niclosamide ethanolamine salt alleviates PF by modulating the PI3K/mTORC1 pathway and reducing fibroblast proliferation and ECM deposition. 154 Similarly, pharmacological inhibition of mTOR using agents such as rapamycin attenuates fibroblast activation and collagen synthesis, highlighting the therapeutic potential of targeting this pathway. 153

2.5.5 Hippo/Yes‐associated protein pathway

The Hippo/Yes‐associated protein (YAP) pathway involves a cascade of signaling proteins that regulate cell proliferation, apoptosis, and differentiation. When dysregulated, the Hippo pathway leads to the activation of the YAP and transcriptional coactivator with PDZ‐binding motif (TAZ), which translocates to the nucleus and drives the expression of profibrotic genes. 155

In PF, YAP/TAZ activation is frequently observed in epithelial and mesenchymal cells. Notably, YAP/TAZ is significantly upregulated in fibrotic lung tissues. 156 The crosstalk between YAP/TAZ and other signaling pathways, such as TGF‐β, is also vital. TGF‐β signaling is a major driver of fibrosis and can activate YAP/TAZ independently of the canonical Hippo pathway. This interaction creates a feedback loop that enhances the fibrotic response. For instance, YAP/TAZ can enhance the transcription of TGF‐β target genes, further promoting fibroblast activation and ECM production. 157 Pharmacological inhibition of the Hippo/YAP pathway has shown promise in preclinical studies. Compounds which inhibit YAP/TAZ activity, such as verteporfin, have been shown to reduce fibrosis by preventing the nuclear translocation of these transcriptional coactivators. 158 In addition, icariin, a natural flavonoid, attenuates bleomycin‐induced PF by targeting the Hippo/YAP pathway, thereby reducing fibroblast activation and ECM deposition. 159 Moreover, the metabolic regulation of the Hippo/YAP pathway plays a role in fibrosis. Notably, glycolysis and lactate production influence YAP/TAZ activity. For instance, increased lactate levels in fibrotic lungs contribute to YAP/TAZ activation, which, in turn, drives the expression of profibrotic genes. This metabolic–epigenetic interaction highlights the complexity of fibrosis regulation and the potential for targeting metabolic pathways in conjunction with Hippo/YAP signaling. 160 , 161

2.5.6 Notch signaling pathway

Notch signaling involves Notch receptors (Notch1−4) and their ligands (Jagged1, Jagged2, Delta‐like1, Delta‐like4), which facilitate cell‐to‐cell communication and transcriptional regulation upon activation. 162 In PF, Notch signaling is aberrantly activated, contributing to the transition of various cell types such as fibroblasts and pericytes into myofibroblasts, which are pivotal for ECM deposition and tissue remodeling. Notably, Notch1 promotes pericyte‐to‐myofibroblast transition through the PDGFR/ROCK1 signaling pathway, enhancing fibroblast proliferation and differentiation, and exacerbating fibrosis. 163

The crosstalk between Notch and TGF‐β signaling pathways amplifies the fibrotic response. TGF‐β upregulates Notch receptors and ligands, thereby enhancing Notch signaling activity. Additionally, Notch3 deficiency attenuates PF and impedes lung function decline, indicating the distinct roles of different Notch receptors in fibrosis. 164 This highlights the importance of specific targeting of the Notch signaling pathway to achieve effective therapeutic outcomes.

2.5.7 Oxidative stress

Oxidative stress plays significant roles in the pathogenesis of PF. ROS, primarily generated in the mitochondria and by NADPH oxidases (NOXs), are essential for normal cellular functions but can lead to tissue damage when produced in excess. 165 In PF, excessive ROS production contributes to epithelial cell injury, fibroblast activation, and ECM remodeling, thereby exacerbating the fibrotic process. 165 For instance, NOX2 and NOX4 are upregulated in PF, leading to increased ROS levels that activate pathways involving p53, Caspase‐3, and NF‐κB, promoting apoptosis and fibrosis. 165 ROS‐induced damage in PF involves multiple mechanisms, including the induction of mitochondrial dysfunction, lipid peroxidation, DNA damage, and activation of profibrotic signaling pathways. 166 ROS can enhance the activation of TGF‐β1 by promoting its release and activation from latent complexes in the ECM. This, in turn, stimulates myofibroblast differentiation and collagen production, further driving the fibrotic process. 165 The role of oxidative stress is also evident in the upregulation of lung ornithine aminotransferase, which regulates mitochondrial ROS generation and TGF‐β1 activity, linking metabolic pathways to the fibrotic response. 167 SLC15A3 plays a crucial role in regulating oxidative stress in macrophages. The deficiency of SLC15A3 protects against PF by enhancing the macrophage antioxidant stress response via the p62–NRF2 pathway. 168 This regulation helps maintain homeostasis of the pulmonary microenvironment and inhibits the progression of fibrosis.

2.5.8 Autophagy and apoptosis

Dysregulation of the autophagy and apoptosis pathways can lead to the accumulation of damaged cells and ECM components, contributing to fibrosis. Autophagy‐related proteins such as LC3 and Beclin‐1 have been shown to play roles in fibroblast activation and survival. 169 Impaired autophagy can lead to accumulation of dysfunctional organelles and increased cellular stress, thereby promoting fibrosis. Selective deletion of Atg5 in AT2 cells resulted in defective alveolar epithelial repair and worsen fibrosis after bleomycin. 170 Conversely, excessive apoptosis of epithelial cells can exacerbate tissue injury and inflammation, further promoting fibrosis. 171

2.5.9 Epigenetic modifications

Epigenetic modifications, including DNA methylation, histone modifications, and RNA‐based mechanisms, collectively regulate the transcriptional landscape of fibrotic lung tissues.

DNA methylation, particularly at CpG islands in gene promoters, plays a crucial role in silencing antifibrotic genes and promoting fibrotic gene expression. Aberrant DNA methylation patterns have been observed in IPF, including the hypermethylation of antifibrotic genes and the hypomethylation of profibrotic genes. This dysregulation promotes fibroblast activation and myofibroblast differentiation, key processes in ECM deposition and fibrosis progression. 172

Histone modifications, including acetylation, methylation, and lactylation, also significantly contribute to PF. Histone lactylation, a relatively novel modification, induces a profibrotic phenotype in macrophages by upregulating genes such as ARG1, OPN, and PDGFA. This modification is mediated by p300, an acetyltransferase that facilitates lactylation of histone lysine residues and enhances the transcription of profibrotic genes. 173 Increased lactate levels from augmented glycolysis in fibrotic lungs drive this process, highlighting the metabolic–epigenetic crosstalk in fibrosis.

RNA modifications, particularly N6‐methyladenosine (m6A) modifications, have been implicated in the development of PF. 174 m6A modifications affect RNA stability and translation, influencing the expression of genes involved in fibrosis. For instance, the m6A reader protein YTHDC1 delays cellular senescence and PF by activating ATR, a critical DNA damage response protein, in an m6A‐independent manner. This suggests that RNA modifications play a role in the maintenance of cellular homeostasis and mitigation of fibrotic processes. 174

3 CURRENT DIAGNOSTIC TOOLS AND BIOMARKERS

3.1 Radiological imaging

Radiological imaging is crucial in the diagnosis and assessment of PF. High‐resolution computed tomography (HRCT) is the gold standard for providing detailed images of the lung parenchyma and for identifying patterns characteristic of interstitial lung diseases (ILDs). 175 HRCT is essential for diagnosing IPF, revealing specific patterns such as usual interstitial pneumonia. 9 Although not routinely used for PF diagnosis, magnetic resonance imaging (MRI) offers functional imaging data, and advanced techniques, such as hyperpolarized gas MRI, enhance lung function assessment. Positron emission tomography (PET), particularly PET/computed tomography, assesses metabolic activity and inflammation to guide prognosis and therapy. 176 , 177 AI in radiological imaging is advancing, with algorithms analyzing HRCT scans to detect early fibrosis or disease progression, thereby improving the identification and quantification of fibrotic changes. 178

3.2 Pulmonary function tests

Pulmonary function tests (PFTs) are essential for diagnosing and monitoring PF as they provide quantitative measures of lung function, which are crucial for assessing disease severity and progression. Specifically, forced vital capacity (FVC) is a key parameter in PFTs used to assess the restrictive lung defect characteristics of PF. 178 A decline in FVC over time is a critical indicator of disease progression and is commonly used as a primary endpoint in clinical trials of PF treatment. Monitoring FVC helps clinicians evaluate the effectiveness of therapeutic interventions and make informed decisions regarding patient management. 178 Additionally, the diffusing capacity of the lungs for carbon monoxide (DLCO) measures the ability of the lungs to transfer gas from inhaled air to the bloodstream. Reduced DLCO is a hallmark of PF and reflects an impaired gas exchange capacity due to fibrosis. 179 Serial DLCO measurements provide valuable information regarding disease progression and treatment responses. The 6‐minute walk test (6MWT) assesses exercise tolerance and functional capacity in patients with PF by measuring the distance a patient can walk on a flat, hard surface in 6 min. This test is useful for evaluating the impact of PF on daily activities and overall functional status. A decline in the 6MWT distance is linked to worse outcomes and serves as a prognostic marker in clinical practice. 180

3.3 Biomarkers

Biomarkers are pivotal in differentiating PF from other ILDs and assessing disease activity. These markers can be categorized based on their roles in various biological processes.

3.3.1 Fibrogenesis and ECM remodeling markers

MMPs, particularly MMP‐1, MMP‐7, and MMP‐8, are significantly elevated in patients with PF and are involved in ECM degradation and remodeling. 181 , 182 MMP‐7, in particular, correlates with disease severity and progression, making it a promising biomarker. 183 Elevated baseline MMP‐7 levels predict overall mortality and disease progression in untreated patients with IPF, independent of age, sex, smoking status, and lung function, as shown by a robust individual participant data meta‐analysis. 184 Other markers such as periostin and osteopontin are also associated with fibrosis and ECM remodeling, reflecting ongoing fibrotic activity and matrix turnover. 185 , 186

3.3.2 Alveolar epithelial cell injury markers

Levels of Krebs von den Lungen‐6 (KL‐6), surfactant proteins (SP‐A and SP‐D), and receptors for advanced glycation end‐products are elevated in patients with PF and reflect alveolar epithelial cell damage and repair processes. 141 , 187 , 188 KL‐6 levels correlate with disease severity, extent of fibrosis, and prognosis. Elevated SP‐A and SP‐D levels are indicative of alveolar damage and inflammation in PF, and are used to differentiate PF from other lung diseases and assess disease progression. 189

3.3.3 Inflammatory and immune dysfunction markers

Markers such as YKL‐40, S100A8/A9, and CCL18 are elevated in PF and are involved in chronic inflammation and immune response dysregulation. These markers can indicate disease activity and predict disease exacerbation. 141 , 190 YKL‐40 is associated with macrophage activation and tissue remodeling, whereas S100A8, S100A9, and S100A12 serve as biomarkers for inflammation and fibrosis, offering potential targets for monitoring disease activity and prognosis. 141 Elevated levels of these proteins in the peripheral blood correlate with disease progression.

Machine learning‐based approaches have identified differentially expressed genes such as FHL2, HPCAL1, RNF182, and SLAIN1 as potential biomarkers for PF. 191 These biomarkers were validated using various machine learning models, including LASSO logistic regression, support vector machine‐recursive feature elimination, and random forest algorithms. The integration of machine learning with biomarker discovery is a powerful tool for improving diagnostic accuracy and understanding disease mechanisms. 191 scRNA‐seq and proteomic and metabolomic analyses have provided detailed insights into cellular heterogeneity by identifying specific cell populations and their associated gene expression profiles in PF lungs. These techniques help to identify cell‐specific biomarkers and understand the role of different cell types in disease progression. 192

4 THERAPEUTIC STRATEGIES AND EMERGING TREATMENTS

4.1 Anti‐inflammation treatments

Traditional treatments for IPF include immunosuppressants and glucocorticoids. These therapies aim to reduce inflammation and immune system activity, which are hypothesized to mitigate fibrosis progression. However, extensive clinical studies have shown their limited efficacy and potential adverse effects, leading to a decline in their routine use. 5 Immunosuppressants, such as azathioprine and cyclophosphamide, were initially used based on the belief that IPF has an autoimmune component. Similarly, glucocorticoids, such as prednisone, have been employed to suppress inflammation. 5 However, current guidelines generally recommend against their use in IPF, except in specific situations, such as managing acute exacerbations.

4.2 Pirfenidone and nintedanib

Pirfenidone is an oral antifibrotic agent that inhibits the synthesis of TGF‐β and other cytokines, reducing fibroblast proliferation and collagen synthesis. 144 Clinical trials have shown that pirfenidone reduces lung function decline and improves progression‐free survival (Table 1). It also possesses anti‐inflammatory and antioxidant properties that contribute to its therapeutic effects. 193 Common side effects include gastrointestinal disturbances, photosensitive rashes, and elevated liver enzyme levels, which necessitate regular monitoring. 194

TABLE 1 Summary of clinical trials on nintedanib from the past 5 years.

	Conditions	Phase	Treatment duration	Outcome	
Kim et al. 195	IPF	Phase 3	24 months	Overall survival and nonelective respiratory hospitalizations did not differ significantly between the pirfenidone and nintedanib groups.	
Wijsenbeek et a.l 175	PPF	Phase 3	24 months	Mitigated the progression of dyspnea, fatigue, cough, and ILD effects	
Inoue et al. 196	PF‐ILD	Phase 3	52 weeks	Lessen symptom progression and the impacts of PF‐ILD	
Deterding et al. 197	ChILD	Phase 3	24 weeks	In children and adolescents with fibrosing ILD, nintedanib dosing was safely tolerated.	
Matteson et al. 198	RA‐ILD	Phase 3	24 months	Slowed FVC decline, with few adverse events	
Cottin et al. 199	PF‐ILD	Phase 3	52 weeks	Immunomodulatory therapies did not affect the efficacy of nintedanib in reducing FVC decline.	
Inoue et al. 200	PF‐ILD	Phase 3	52 weeks	Slowed the progression of ILD in Japanese patients, slowed FVC decline	
Schmid et al. 201	PF‐ILD and SSc‐ILD	Phase 2/Phase 3	52 weeks	Nintedanib exposure correlated with ALT or AST elevations.	
Kuwana et al. 202	SSc‐ILD	Phase 3	52 weeks	Nintedanib slowed ILD progression in both Japanese and non‐Japanese patients with SSc‐ILD, with no subgroup heterogeneity.	
Richeldi et al. 203	IPF	Phase 3	24 weeks	Nintedanib slowed FVC decline and safety in IPF patients with different levels of gas exchange impairment.	
Wells et al. 204	PF‐ILD	Phase 3	52 weeks	Nintedanib reduces ILD progression, measured by FVC decline, in patients with chronic fibrosing ILD, regardless of diagnosis.	
Song et al. 205	IPF	Phase 3	52 weeks	Nintedanib sustainably slows IPF progression in Asian patients with acceptable long‐term safety and tolerability.	
Moor et al. 206	IPF	NA	24 weeks	Home monitoring did not improve overall HRQOL (K‐BILD) but tended to boost psychological well‐being and allowed tailored medication adjustments.	
Abbreviations: PPF, progressive pulmonary fibrosis; PF‐ILD, progressive fibrosing interstitial lung disease; ChILD, childhood interstitial lung disease; RA‐ILD, rheumatoid arthritis develops interstitial lung disease; FVC, forced vital capacity; SSc‐ILD, systemic sclerosis‐associated ILD; NA, not applicable; HRQOL, health‐related quality of life; K‐BILD, king's brief interstitial lung disease questionnaire.

Data resource: https://www.clinicaltrials.gov.

John Wiley & Sons, Ltd.

Nintedanib is a tyrosine kinase inhibitor that targets multiple pathways involved in fibrosis, including VEGF, PDGF, and FGF receptors. 207 It significantly slows the decline in FVC in patients with IPF by inhibiting fibroblast proliferation, migration, and transformation into myofibroblasts (Table 2). 207 The side effects of nintedanib primarily include gastrointestinal symptoms, particularly diarrhea, and elevated liver enzyme levels, requiring dose adjustments and monitoring. 208

TABLE 2 Summary of clinical trials on pirfenidone from the past 5 years.

	Conditions	Phase	Treatment duration	Outcome	
Solomon et al. 209	RA‐ILD	Phase 2	52 weeks	Slowed FVC decline, with few adverse events	
Behr et al. 210	PF‐ILD	Phase 2	48 weeks	Slow disease progression, a reduced decline in FVC	
Behr et al. 211	PF‐uILD	Phase 2	24 weeks	Pirfenidone is less effective in PF‐uILD patients on MMF but beneficial for those not on MMF, regardless of corticosteroid use. It was well tolerated with or without MMF and corticosteroids.	
Sakamoto et al. 212	IPF	Phase 3	48 weeks	Combining inhaled N‐acetylcysteine and pirfenidone may worsen IPF.	
Behr et al. 213	IPF	Phase 2	52 weeks	Adding sildenafil to pirfenidone offered no additional treatment benefits for advanced IPF patients with pulmonary hypertension risk, and no new safety issues were noted.	
Blackwell et al. 214	IPF	Phase 1	12 weeks	Pirfenidone is safe and well tolerated when combined with valganciclovir.	
Blackwell et al. 215	PF‐uILD	Phase 2	24 weeks	Pirfenidone may benefit patients with PF‐uILD and has an acceptable safety profile	
Ikeda et al. 216	IPF	Phase 3		Serum SP‐D was the key biomarker for pirfenidone efficacy in the IPF trial, with potential as a pharmacodynamic biomarker	
Abbreviations: PF‐uILD, progressive fibrosing unclassifiable interstitial lung disease; MMF, mycophenolate mofetil.

Data resource: https://www.clinicaltrials.gov.

John Wiley & Sons, Ltd.

4.3 Supportive care

Pulmonary rehabilitation programs are designed to improve the physical and emotional wellbeing of patients with chronic respiratory diseases. These programs typically include exercise training, nutritional counseling, education on lung diseases, and breathing techniques. 217 Pulmonary rehabilitation improves exercise capacity, reduces symptoms, and enhances the quality of life in patients with IPF. 217 Oxygen therapy is prescribed to patients with IPF with resting or exertional hypoxemia to improve oxygenation and reduce the symptoms of breathlessness. 218 Noninvasive ventilation may be used to support breathing in more advanced cases, particularly during acute exacerbations or in patients with concurrent sleep apnea. 219 These interventions help to maintain adequate oxygen levels and reduce breathing.

4.4 Lung transplantation

Lung transplantation is considered for eligible patients with IPF and advanced disease refractory to medical therapy. This remains the only intervention that can significantly improve the survival and quality of life of selected patients. However, this procedure is associated with significant risks and requires lifelong immunosuppression to prevent organ rejection. 220 Careful patient selection and management are essential to optimize patient outcomes.

4.5 Emerging treatments

4.5.1 Targeting the immune response

Pharmacological interventions targeting the immune system in PF focus on modulating cytokines, immune checkpoints, and macrophages, and utilizing cellular therapies and precision medicine approaches. Cytokines, such as those targeting TGF‐β, IL‐6, IL‐1β, and IL‐13, play a central role in limiting fibrotic and inflammatory signaling pathway activities. 221 For instance, fresolimumab inhibits TGF‐β, while tocilizumab and canakinumab target IL‐6 and IL‐1β, respectively. Monoclonal antibodies such as lebrikizumab and tralokinumab inhibit IL‐13 and reduce fibroblast activity and collagen deposition. 221 Immune checkpoint inhibitors, including PD‐1/PD‐L1 inhibitors (nivolumab and pembrolizumab) and CTLA‐4 inhibitors (ipilimumab), have been explored for their potential to modulate immune responses and reduce fibrosis by enhancing the immune system activity against fibrotic tissues. 222 Macrophage modulation involves the targeting of M2 macrophage polarization and monocyte recruitment. 223 Agents such as dexamethasone modulate M2 macrophage activity, whereas cenicriviroc, a CCR2/CCR5 inhibitor, limits macrophage infiltration and reduces the fibrotic response. 105 Cellular therapies, particularly T cell‐based therapies involving adoptive cell transfer or engineered T cells, aim to enhance the antifibrotic properties of immune cells. 224 Precision medicine approaches utilize biomarker‐driven therapies and genetic/epigenetic modulation to tailor treatment to individual patient profiles. Advanced diagnostic techniques such as scRNA‐seq can identify specific cytokine profiles or immune cell populations for targeted interventions. Genetic and epigenetic therapies, including gene‐editing technologies and epigenetic drugs, aim to reprogram immune cells to reduce fibrosis by targeting the underlying factors that contribute to immune dysregulation. Overall, these multifaceted strategies aim to reduce inflammation, modulate immune responses, and slow or reverse the fibrotic process in patients with PF, thereby offering hope for improved patient outcomes. This comprehensive approach highlights the potential of immune‐targeted therapies to transform the treatment landscape for PF, addressing the complex interplay of immune mechanisms driving the disease, and paving the way for novel and effective treatments.

4.5.2 Targeting fibrosis

Antifibrotic treatments for PF focus on key pathways that drive fibroblast activation, ECM accumulation, and collagen production. 225 Transforming growth factor‐beta (TGF‐β) is a central mediator in fibrosis, and therapies targeting TGF‐β signaling, such as pamrevlumab, a monoclonal antibody against CTGF, reduce fibrosis and improve lung function. 226 CTGF, induced by TGF‐β, is crucial in fibroblast activation and ECM production. The direct targeting of fibroblasts is another strategy. Integrin inhibitors, like those targeting integrin αvβ6, prevent the activation of latent TGF‐β, thereby reducing fibroblast activation and ECM deposition. 227 Serine/threonine kinase inhibitors block the signaling pathways essential for fibroblast proliferation and myofibroblast differentiation, thereby hindering the fibrotic process. 228 , 229

ECM remodeling is another critical aspect of fibrosis. MMPs inhibitors regulate ECM turnover, prevent excessive matrix accumulation, and mitigate tissue remodeling, contributing to fibrosis progression. 230 Targeting collagen production, a hallmark of fibrosis, can be achieved by inhibiting enzymes such as prolyl 4‐hydroxylase, thereby reducing collagen stability and accumulation. 231

These antifibrotic strategies aim to disrupt the signals and processes that drive fibrosis in PF. By targeting TGF‐β signaling, fibroblast activation, ECM remodeling, and collagen production, these therapies show promise in slowing disease progression and improving patient outcomes. Continued research and clinical trials are essential to optimize these treatments and develop new agents to combat the fibrotic processes underlying PF, ultimately improving the quality of life of patients.

4.5.3 Targeting senescence

Recent advances in the understanding of the pathophysiology of PF have highlighted the critical role of cellular senescence in driving fibrosis. Senescent cells exhibit a proinflammatory and profibrotic phenotype, known as the senescence‐associated secretory phenotype (SASP), which perpetuates tissue damage and fibrosis. Targeting cellular senescence has emerged as a promising therapeutic strategy for PF. 232

Sirtuins, particularly SIRT3, play a significant role in modulating cellular senescence and fibrosis. Studies show that SIRT3 expression is markedly reduced in the lungs of patients with IPF and aged mice with persistent fibrosis. 233 Restoring SIRT3 enhances fibrosis resolution by activating the FoxO3a transcription factor and re‐establishing susceptibility to apoptosis in myofibroblasts. 234 SIRT3 activation mitigates epithelial cell senescence via the cGAS–STING pathway, thereby reducing fibrosis and improving lung function. 233 Bone morphogenetic protein 4 (BMP4) inhibits PF by modulating senescence and mitophagy of lung fibroblasts. BMP4 administration in fibrotic mouse models decreases senescence markers and enhances mitophagy, leading to reduced fibrosis. 235 Notably, senotherapeutics that target senescent cells to alleviate fibrosis show promise. For example, compounds such as navitoclax and dasatinib induce apoptosis in senescent cells and reduce fibrosis in mouse models. 232 Inhibition of the SASP, which is characterized by proinflammatory cytokines and growth factors, also ameliorates fibrosis. Targeting key SASP components, such as IL‐1α, IL‐6, and TGF‐β, significantly reduces fibrosis and improves tissue regeneration. 232 Enhancing mitophagy using pharmacological agents or genetic manipulation reduces senescence and fibrosis in lung fibroblasts. The activation of PINK1/Parkin‐mediated mitophagy decreases the expression of senescence and fibrotic markers. 235 Additionally, honokiol, a natural compound, activates SIRT3 and reduces fibrosis via the cGAS‐STING pathway. 233

4.5.4 Targeting metabolism

PF is characterized by significant metabolic reprogramming, primarily driven by TGF‐β, which induces shifts toward increased glycolysis and mitochondrial dysfunction. This reprogramming process involves increased glycolytic enzyme expression, glucose transporter levels, and lactate production in fibroblasts, alveolar epithelial cells, and macrophages. 160 Targeting these metabolic alterations may offer a novel therapeutic approach for PF.

Mitochondrial transplantation restores mitochondrial function, reverses the fibrotic phenotype, reduces glycolytic enzyme expression and lactate production, and increases ATP production. 236 Modulation of lipid metabolism is another strategy, as dysregulated lipid metabolism contributes to PF. Promotion of fatty acid oxidation can mitigate fibrotic responses. 237 Inhibiting glycolysis, using agents such as with 2‐deoxy‐d‐glucose (2‐DG) and targeting glycolytic regulators such as hypoxia‐inducible factor‐1 alpha, can reduce fibrosis. 238 , 239

Iron oxide nanoparticles enhance intercellular mitochondrial transfer, improve mitochondrial function, and reduce fibrosis. 240 The modulation of macrophage metabolism can also reduce profibrotic activity. 241 Addressing mitochondrial dynamics by promoting fusion and inhibiting excessive fission restores mitochondrial integrity and reduces fibrosis. 242 These strategies offer promising avenues for the treatment of PF by targeting metabolic underpinnings.

4.5.5 Cell‐based therapies

Cell‐based therapies for PF, focusing on the regeneration and repair of lung tissue through the transplantation of various cell types, have shown promising results. The most studied cell types used in these therapies include AT2, mesenchymal stromal cells (MSCs), induced pluripotent stem cells (iPSCs), and distal airway stem cells (DASCs). These therapies aim to restore lung function, reduce fibrosis, and improve the overall outcomes in patients with PF.

AT2 cells play a crucial role in maintaining alveolar homeostasis and repairing the damaged alveolar epithelium. Meta‐analyses have shown that AT2 transplantation significantly improves blood oxygen saturation, reduces lung hydroxyproline content, and decreases lung weight in mouse models of PF. 243 These cells exhibit stem cell properties, allowing them to proliferate and transdifferentiate into AT1 cells, thereby restoring the integrity of the alveolar–capillary barrier and promoting lung regeneration. 243

MSCs are another cell type that have been extensively investigated for their potential in the treatment of PF. MSCs can differentiate into multiple cell types, including alveolar epithelial cells and fibroblasts, and they secrete various bioactive molecules that modulate immune responses, reduce inflammation, and promote tissue repair. Notably, MSCs can attenuate AT2 cell senescence by regulating NAMPT‐mediated NAD metabolism, which is critical for maintaining cellular energy balance and reducing oxidative stress. 244 , 245 Furthermore, MSCs can inhibit myofibroblast differentiation of lung fibroblasts, thereby reducing fibrosis and improving lung function. 246

iPSCs offer a versatile approach for PF treatment because of their ability to differentiate into any cell type. In mouse models of PF, iPSC‐derived alveolar epithelial cells have been shown to reduce fibrosis, restore lung structure, and improve lung function by modulating the WNT signaling pathway, which is essential for tissue repair and regeneration. 247 Additionally, iPSCs can be used to generate patient‐specific cell lines, providing a personalized therapeutic approach and reducing the risk of immune rejection.

DASCs represent a relatively new focus in PF research. These cells can migrate to injured areas of the lung, where they can proliferate and differentiate into both alveolar and airway epithelial cells. DASCs have been shown to ameliorate bleomycin‐induced PF in mice by restoring the integrity of the lung epithelium and reducing inflammation and fibrosis. 248 Their ability to self‐renew and differentiate into multiple lung cell types makes them promising candidates for regenerative therapy of PF.

Cell‐based therapies for PF offer a multifaceted treatment approach that targets different aspects of the disease process. AT2 cells focus on repairing and maintaining the alveolar epithelium; MSCs modulate the immune response and reduce fibrosis; iPSCs provide a versatile and personalized approach for lung regeneration; and DASCs offer robust regenerative potential. These therapies, either alone or in combination, hold significant promise for improving outcomes in patients with PF, moving closer to effective treatments and potentially reversing the progression of this debilitating disease. Further research and clinical trials are required to optimize these therapies, determine the best cell sources, and establish standardized protocols for their application in patients.

4.5.6 Gene therapy

Gene therapy represents a promising avenue for treating PF by specifically targeting and modifying the key molecular pathways involved in disease progression. An innovative approach involves the use of adeno‐associated virus (AAV)‐mediated delivery systems. Notably, AAV9 vectors have been employed to deliver S1P lyase (SGPL1) directly into lung tissues, effectively reducing sphingosine‐1‐phosphate (S1P) levels. This reduction in S1P, a lipid mediator known to exacerbate fibrosis and inflammation, attenuates fibrotic signaling and decreases collagen deposition, thereby improving lung function in mouse models of BLM‐induced lung injury. 249 Furthermore, AAV‐SGPL1 therapy reduces the expression of profibrotic markers such as TNFα, IL‐1β, fibronectin, and various collagen genes, demonstrating significant potential to modify the disease course by disrupting critical profibrotic pathways. 249

Another promising strategy involves the combination of hepatocyte growth factor (HGF) with TGF‐β/Smad inhibitors, delivered via AAV9 vectors. This combination therapy has demonstrated efficacy in mouse models of silicosis by reducing fibrosis, promoting epithelial repair, and inhibiting myofibroblast differentiation. HGF facilitates the regeneration of lung epithelial cells, while TGF‐β/Smad inhibitors block pathways that contribute to fibrosis, resulting in synergistic effects that further ameliorate lung damage and improve respiratory function. 250

Advancements in gene delivery technologies have also played crucial roles in enhancing the effectiveness of gene therapies for PF. Liposome‐based gene delivery systems have been developed to improve the uptake and expression of therapeutic genes in lung tissues. For instance, local administration of Plekhf1 gene therapy using liposomal carriers has shown the potential to reduce fibrotic responses and improve lung architecture by modulating the cellular mechanisms involved in fibrosis. 251 In addition, perfluorocarbon nanoemulsions have been used to enhance the delivery of siRNAs targeting fibrotic genes. These nanoemulsions facilitate the efficient transport of siRNA into lung cells, thereby enhancing gene silencing and reducing fibrosis. The unique properties of perfluorocarbons, such as their ability to increase the bioavailability and stability of therapeutic siRNAs in the lung microenvironment, support their use in gene therapy. 252

Overall, gene therapy offers a multifaceted approach to combat PF by addressing the underlying molecular mechanisms that drive fibrosis. AAV vectors, particularly AAV9, provide a versatile platform for delivering therapeutic genes with high specificity and sustained expression. The combination of gene therapies targeting multiple pathways, along with advanced delivery systems, such as liposomal carriers and nanoemulsions, holds significant promise for improving clinical outcomes in patients with PF. As research continues, these approaches are expected to be refined and optimized, paving the way for effective gene‐based treatments that can halt or even reverse PF progression. Further studies and clinical trials are necessary to validate the efficacy and safety of these therapies in patients, ultimately aiming to provide hope for those suffering from this debilitating condition.

4.5.7 Traditional Chinese medicine

Traditional Chinese medicine (TCM) has been explored as a therapeutic approach for PF, and several studies have highlighted its potential benefits. One such formulation, Bufei Huoxue (BFHX) capsules, comprises components of Astragalus membranaceus, Paeonia lactiflora, and Psoralea corylifolia and has shown efficacy in alleviating PF through various mechanisms. 253 In a mouse model of bleomycin‐induced PF, BFHX treatment significantly reduced fibrosis, improved lung function, and decreased inflammation. Treatment with BFHX led to a notable reduction in IL‐6 and TNF‐α levels, which are key inflammatory cytokines implicated in the pathogenesis of PF. 253 Additionally, BFHX treatment upregulated the expression of E‐cadherin and downregulated α‐SMA, collagen I, vimentin, and fibronectin, indicating its role in inhibiting ECM deposition. The underlying mechanism involves the inhibition of the TGF‐β1/Smad2/3 signaling pathway, which is crucial for the transition of fibroblasts to myofibroblasts and the progression of fibrosis. 253

Other TCM compounds have demonstrated potential antifibrotic effects. Similarly, Psoralen, a compound isolated from P. corylifolia, attenuates fibroblast activation and collagen deposition. 254 These findings suggest that TCM formulations, such as BFHX and its individual components, offer a multifaceted approach to combating PF by modulating critical pathways involved in fibrosis and inflammation.

Studies have explored the combined use of TCM and conventional pulmonary drug delivery systems to enhance therapeutic outcomes. For example, integrating TCM formulations with inhalation therapies can improve drug bioavailability and target specific lung regions affected by fibrosis. This approach not only leverages the therapeutic benefits of TCM but also enhances the precision and efficacy of treatment modalities for PF. 255

In summary, TCM formulations such as BFHX capsules hold significant promise for PF treatment. By targeting key inflammatory and fibrotic pathways, these formulations reduce fibrosis, improve lung function, and enhance overall patient outcomes. Future research should focus on elucidating the molecular mechanisms of TCM, optimizing delivery systems, and conducting large‐scale clinical trials to fully elucidate the therapeutic potential of these ancient remedies in modern medicine.

5 CONCLUSION AND PROSPECTS

This review highlights that PF involves multiple factors, including epithelial cells, mesenchymal cells, immune responses, and microorganisms. These elements interact with and modify various pathways simultaneously, necessitating a systematic and integrative research approach. Future research on the mechanisms, diagnostics, and therapies should incorporate advanced technologies, such as single‐cell sequencing, organoid cultures, and metabolomics (Figure 3). Single‐cell sequencing can be used to identify the unique contributions of specific cell types to the lung microenvironment. Organoid cultures replicate the three‐dimensional structure and function of the lung tissue, providing a more physiologically relevant model for studying disease mechanisms and testing treatments. Metabolomics can reveal changes in metabolic pathways that contribute to disease progression, whereas microbiology can elucidate the role of microorganisms in PF. These studies should be integrated within a systems biology framework to capture the intricate interactions and regulatory networks involved in PF.

FIGURE 3 A panoramic understanding of PF toward comprehensive multitargeted interventions. This figure illustrates the interconnected and mutually reinforcing relationship between the study of mechanisms, diagnosis, and treatment of PF. The cycle begins with understanding the mechanisms underlying PF, which leads to the formulation of novel hypotheses. These hypotheses drive the development of new diagnostic tools and classification efforts, enhancing the ability to identify and treat the disease accurately. The insights gained from diagnostics inform therapeutic strategies, leading to novel interventions that improve patient outcomes. As new therapies are implemented, they provide feedback that refines our understanding of the mechanisms and diagnostics, thus continuing the cycle of innovation and improvement. Throughout this process, various omics technologies are utilized to explore and elucidate the complexities of PF, ensuring a comprehensive and detailed approach to its study and management. This figure was designed using BioRender (https://biorender.com/).

Early and accurate diagnosis is crucial for effective management of PF. Future efforts should focus on the discovery and clinical application of new biomarkers to detect this disease in its early stages. Advanced imaging techniques and molecular diagnostics can be used to monitor disease progression and evaluate treatment responses. Reliable biomarkers can facilitate personalized treatment strategies, allowing timely and targeted interventions to slow or halt disease progression.

Because of the multifactorial nature of PF, a single therapeutic approach is often inadequate. Therefore, a combination of treatments that target multiple pathways and cellular interactions should be considered. Combining antifibrotic drugs with cell and gene therapies, as well as leveraging nanoparticles and gene‐editing technologies, can enhance treatment precision and efficacy. Exploring the synergistic effects of various therapies can improve therapeutic outcomes and reduce adverse effects. Supportive measures such as lifestyle modifications, pulmonary rehabilitation, and oxygen therapy should be incorporated to improve the overall quality of life of patients.

In summary, the pathogenic mechanisms underlying PF are complex and involve numerous cellular interactions and pathways. Future research should adopt a systematic and integrative approach to uncover the intricate details of PF pathogenesis. Early diagnosis using novel biomarkers and advanced imaging techniques coupled with multimodal treatment strategies holds promise for significantly improving patient outcomes. By embracing advanced research tools and comprehensive therapeutic approaches, substantial progress can be made in understanding and treating this challenging disease, ultimately bringing hope to patients.

AUTHOR CONTRIBUTIONS

Yu Zhu, Hongzhi Yu, and Huaiyong Chen conceptualized the manuscript and oversaw the writing process. Jianhai Wang, Kuan Li, and De Hao were responsible for drafting and revising the manuscript. Xue Li contributed by editing the manuscript and compiling relevant research summaries. All authors reviewed and approved the final version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of financial interest.

ETHICS STATEMENT

Not applicable.

ACKNOWLEDGMENTS

This research received funding from the National Natural Science Foundation of China (82100077, 82070001, and 82400091), Tianjin second batch of health industry high‐level talent selection and training project (TJSQNYXXR‐D2‐070, TJSJMYXYC‐D2‐012), Natural Science Foundation of Tianjin (21JCZDJC00430, 21JCQNJC00550, and 23JCYBJC01560), Tianjin Science and Technology Plan Project (22JCYBJC00730), Science and Technology Planning Project of Tianjin Municipal Education Commission (2022YGYB14), and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK‐067C).

DATA AVAILABILITY STATEMENT

Not applicable.
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REFERENCES

1 Selman M , Pardo A . When things go wrong: exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases. Eur Respir J. 2021;58 (3 ):2004507.33542060
2 Maher TM , Bendstrup E , Dron L , et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res. 2021;22 (1 ):197.34233665
3 Podolanczuk AJ , Thomson CC , Remy‐Jardin M , et al. Idiopathic pulmonary fibrosis: state of the art for 2023. Eur Respir J. 2023;61 (4 ):2200957.36702498
4 Liu GY , Budinger GRS , Dematte JE . Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. BMJ. 2022;377 :e066354.36946547
5 Guo H , Sun J , Zhang S , Nie Y , Zhou S , Zeng Y . Progress in understanding and treating idiopathic pulmonary fibrosis: recent insights and emerging therapies. Front Pharmacol. 2023;14 :1205948.37608885
6 Bjorklund F , Ekstrom M . Adverse effects, smoking, alcohol consumption, and quality of life during long‐term oxygen therapy: a nationwide study. Ann Am Thorac Soc. 2022;19 (10 ):1677‐1686.35657698
7 Zhu J , Zhou D , Wang J , et al. A causal atlas on comorbidities in idiopathic pulmonary fibrosis: a bidirectional mendelian randomization study. Chest. 2023;164 (2 ):429‐440.36870387
8 Jiang AG . Viral infection and idiopathic pulmonary fibrosis risk: still need more evidence. Chest. 2020;157 (6 ):1687‐1688.32505320
9 Koudstaal T , Funke‐Chambour M , Kreuter M , Molyneaux PL , Wijsenbeek MS . Pulmonary fibrosis: from pathogenesis to clinical decision‐making. Trends Mol Med. 2023;29 (12 ):1076‐1087.37716906
10 Wang J , Li X , Chen H . Organoid models in lung regeneration and cancer. Cancer Lett. 2020;475 :129‐135.32032677
11 Parimon T , Chen P , Stripp BR , et al. Senescence of alveolar epithelial progenitor cells: a critical driver of lung fibrosis. Am J Physiol Cell Physiol. 2023;325 (2 ):C483‐C495.37458437
12 Parimon T , Yao C , Stripp BR , Noble PW , Chen P . Alveolar epithelial type II cells as drivers of lung fibrosis in idiopathic pulmonary fibrosis. Int J Mol Sci. 2020;21 (7 ):2269.32218238
13 Gandhi S , Tonelli R , Murray M , Samarelli AV , Spagnolo P . Environmental causes of idiopathic pulmonary fibrosis. Int J Mol Sci. 2023;24 (22 ):16481.38003670
14 Cui F , Sun Y , Xie J , et al. Air pollutants, genetic susceptibility and risk of incident idiopathic pulmonary fibrosis. Eur Respir J. 2023;61 (2 ):2200777.36137588
15 Andersson M , Blanc PD , Toren K , Jarvholm B . Smoking, occupational exposures, and idiopathic pulmonary fibrosis among Swedish construction workers. Am J Ind Med. 2021;64 (4 ):251‐257.33547652
16 Reynolds CJ , Sisodia R , Barber C , et al. What role for asbestos in idiopathic pulmonary fibrosis? Findings from the IPF job exposures case‐control study. Occup Environ Med. 2023;80 (2 ):97‐103.36635100
17 Gandhi SA , Min B , Fazio JC , et al. The impact of occupational exposures on the risk of idiopathic pulmonary fibrosis: a systematic review and meta‐analysis. Ann Am Thorac Soc; 2024:486‐498.
18 Conti S , Harari S , Caminati A , et al. The association between air pollution and the incidence of idiopathic pulmonary fibrosis in Northern Italy. Eur Respir J. 2018;51 (1 ):1700397.29371377
19 Yue D , Zhang Q , Zhang J , et al. Diesel exhaust PM2.5 greatly deteriorates fibrosis process in pre‐existing pulmonary fibrosis via ferroptosis. Environ Int. 2023;171 :107706.36565570
20 Shen H , Zheng R , Du M , Christiani DC . Environmental pollutants exposure‐derived extracellular vesicles: crucial players in respiratory disorders. Thorax. 2024;79 (7 ):680‐691.38631896
21 Douglas D , Keating L , Strykowski R , et al. Tobacco smoking is associated with combined pulmonary fibrosis and emphysema and worse outcomes in interstitial lung disease. Am J Physiol Lung Cell Mol Physiol. 2023;325 (2 ):L233‐L243.37366539
22 Zhu J , Zhou D , Yu M , Li Y . Appraising the causal role of smoking in idiopathic pulmonary fibrosis: a Mendelian randomization study. Thorax. 2024;79 (2 ):179‐181.37217291
23 Zhang Y , Huang W , Zheng Z , et al. Cigarette smoke‐inactivated SIRT1 promotes autophagy‐dependent senescence of alveolar epithelial type 2 cells to induce pulmonary fibrosis. Free Radic Biol Med. 2021;166 :116‐127.33609723
24 Chen L , Sun R , Lei C , Xu Z , Song Y , Deng Z . Alcohol‐mediated susceptibility to lung fibrosis is associated with group 2 innate lymphoid cells in mice. Front Immunol. 2023;14 :1178498.37457733
25 Zou X , Huang Z , Zhan Z , et al. The alcohol extracts of Sceptridium ternatum (Thunb.) Lyon exert anti‐pulmonary fibrosis effect through targeting SETDB1/STAT3/p‐STAT3 signaling. J Ethnopharmacol. 2023;313 :116520.37120058
26 Leuschner G , Klotsche J , Kreuter M , et al. Idiopathic pulmonary fibrosis in elderly patients: analysis of the INSIGHTS‐IPF observational study. Front Med (Lausanne). 2020;7 :601279.33313046
27 Han MK , Murray S , Fell CD , et al. Sex differences in physiological progression of idiopathic pulmonary fibrosis. Eur Respir J. 2008;31 (6 ):1183‐1188.18321929
28 Sese L , Nunes H , Cottin V , et al. Gender differences in idiopathic pulmonary fibrosis: are men and women equal?. Front Med (Lausanne). 2021;8 :713698.34422868
29 Reynolds CJ , Del Greco MF , Allen RJ , et al. The causal relationship between gastro‐oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two‐sample Mendelian randomisation study. Eur Respir J. 2023;61 (5 ):2201585.37080571
30 Huang WJ , Tang XX . Virus infection induced pulmonary fibrosis. J Transl Med. 2021;19 (1 ):496.34876129
31 Wu J , Chen L , Qin C , et al. CD147 contributes to SARS‐CoV‐2‐induced pulmonary fibrosis. Signal Transduct Target Ther. 2022;7 (1 ):382.36424379
32 Sheng G , Chen P , Wei Y , et al. Viral infection increases the risk of idiopathic pulmonary fibrosis: a meta‐analysis. Chest. 2020;157 (5 ):1175‐1187.31730835
33 Jafarian AH , Mohamadian Roshan N , Ayatollahi H , Omidi AA , Ghaznavi M , Gharib M . Epstein‐Barr virus and human herpesvirus 8 in idiopathic pulmonary fibrosis. Iran J Pathol. 2020;15 (1 ):30‐33.32095147
34 Popper H , Stacher‐Priehse E , Brcic L , Nerlich A . Lung fibrosis in autoimmune diseases and hypersensitivity: how to separate these from idiopathic pulmonary fibrosis. Rheumatol Int. 2022;42 (8 ):1321‐1330.34605934
35 Moll M , Peljto AL , Kim JS , et al. A polygenic risk score for idiopathic pulmonary fibrosis and interstitial lung abnormalities. Am J Respir Crit Care Med. 2023;208 (7 ):791‐801.37523715
36 Helling BA , Gerber AN , Kadiyala V , et al. Regulation of MUC5B expression in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;57 (1 ):91‐99.28272906
37 Diaz de Leon A , Cronkhite JT , Katzenstein AL , et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS One. 2010;5 (5 ):e10680.20502709
38 van der Vis JJ , van der Smagt JJ , Hennekam FAM , Grutters JC , van Moorsel CHM . Pulmonary fibrosis and a TERT founder mutation with a latency period of 300 years. Chest. 2020;158 (2 ):612‐619.32315675
39 Peljto AL , Blumhagen RZ , Walts AD , et al. Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants. Am J Respir Crit Care Med. 2023;207 (9 ):1194‐1202.36602845
40 Maitra M , Wang Y , Gerard RD , Mendelson CR , Garcia CK . Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress. J Biol Chem. 2010;285 (29 ):22103‐22113.20466729
41 van Moorsel CH , van Oosterhout MF , Barlo NP , et al. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med. 2010;182 (11 ):1419‐14125.20656946
42 Wang Y , Kuan PJ , Xing C , et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84 (1 ):52‐59.19100526
43 Weaver TE , Conkright JJ . Function of surfactant proteins B and C. Annu Rev Physiol. 2001;63 :555‐578.11181967
44 Zhang D , Adegunsoye A , Oldham JM , et al. Telomere length and immunosuppression in non‐idiopathic pulmonary fibrosis interstitial lung disease. Eur Respir J. 2023;62 (5 ):2300441.37591536
45 Song Z , Yin J , Yao C , et al. Variants in the Toll‐interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population. Crit Care. 2011;15 (1 ):R12.21219635
46 Borie R , Cardwell J , Konigsberg IR , et al. Colocalization of gene expression and DNA methylation with genetic risk variants supports functional roles of MUC5B and DSP in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2022;206 (10 ):1259‐1270.35816432
47 Zhou Y , Zhang Y , Zhao R , et al. Integrating RNA‐Seq with GWAS reveals a novel SNP in immune‐related HLA‐DQB1 gene associated with occupational pulmonary fibrosis risk: a multi‐stage study. Front Immunol. 2021;12 :796932.35111164
48 Allen RJ , Porte J , Braybrooke R , et al. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome‐wide association study. Lancet Respir Med. 2017;5 (11 ):869‐880.29066090
49 Noth I , Zhang Y , Ma SF , et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome‐wide association study. Lancet Respir Med. 2013;1 (4 ):309‐317.24429156
50 Hollmen M , Laaka A , Partanen JJ , et al. KIF15 missense variant is associated with the early onset of idiopathic pulmonary fibrosis. Respir Res. 2023;24 (1 ):240.37777755
51 Krauss E , Gehrken G , Drakopanagiotakis F , et al. Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f‐IPF). BMC Pulm Med. 2019;19 (1 ):130.31319833
52 Zhang D , Povysil G , Newton CA , et al. Genome‐wide enrichment of TERT rare variants in idiopathic pulmonary fibrosis patients of latino ancestry. Am J Respir Crit Care Med. 2022;206 (7 ):903‐905.35666822
53 Borie R , Kannengiesser C , Antoniou K , et al. European Respiratory Society statement on familial pulmonary fibrosis. Eur Respir J. 2023;61 (3 ):2201383.36549714
54 Duckworth A , Gibbons MA , Allen RJ , et al. Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study. Lancet Respir Med. 2021;9 (3 ):285‐294.33197388
55 Chambers RC , Mercer PF . Mechanisms of alveolar epithelial injury, repair, and fibrosis. Ann Am Thorac Soc; 2015:S16‐S20. Suppl 1. Suppl.
56 Yao C , Guan X , Carraro G , et al. Senescence of alveolar type 2 cells drives progressive pulmonary fibrosis. Am J Respir Crit Care Med. 2021;203 (6 ):707‐717.32991815
57 Ishida Y , Kuninaka Y , Mukaida N , Kondo T . Immune mechanisms of pulmonary fibrosis with bleomycin. Int J Mol Sci. 2023;24 (4 ):3149.36834561
58 Zhang Y , Wang J . Cellular and molecular mechanisms in idiopathic pulmonary fibrosis. Adv Respir Med. 2023;91 (1 ):26‐48.36825939
59 Burgoyne RA , Fisher AJ , Borthwick LA . The role of epithelial damage in the pulmonary immune response. Cells. 2021;10 (10 ):2763.34685744
60 Ghonim MA , Boyd DF , Flerlage T , Thomas PG . Pulmonary inflammation and fibroblast immunoregulation: from bench to bedside. J Clin Invest. 2023;133 (17 ):e170499.37655660
61 Ushakumary MG , Riccetti M , Perl AT . Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration. Stem Cells Transl Med. 2021;10 (7 ):1021‐1032.33624948
62 Younesi FS , Miller AE , Barker TH , Rossi FMV , Hinz B . Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat Rev Mol Cell Biol. 2024;25 (8 ):617‐638.38589640
63 Wang Y , Zhang L , Huang T , et al. The methyl‐CpG‐binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation. Eur Respir J. 2022;60 (3 ):2003697.35086828
64 Liu X , Geng Y , Liang J , et al. HER2 drives lung fibrosis by activating a metastatic cancer signature in invasive lung fibroblasts. J Exp Med. 2022;219 (10 ):e20220126.35980387
65 Gabbiani G , Ryan GB , Majne G . Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia. 1971;27 (5 ):549‐550.5132594
66 Homps‐Legrand M , Crestani B , Mailleux AA . Origins of pathological myofibroblasts in lung fibrosis: insights from lineage tracing mouse models in the single‐cell RNA sequencing era. Am J Physiol Lung Cell Mol Physiol. 2023;324 (6 ):L737‐L746.36976924
67 Jiang D , Dey T , Liu G . Recent developments in the pathobiology of lung myofibroblasts. Expert Rev Respir Med. 2021;15 (2 ):239‐247.32981357
68 Valenzi E , Bahudhanapati H , Tan J , et al. Single‐nucleus chromatin accessibility identifies a critical role for TWIST1 in idiopathic pulmonary fibrosis myofibroblast activity. Eur Respir J. 2023;62 (1 ).
69 Fortier SM , Walker NM , Penke LR , et al. MAPK phosphatase 1 inhibition of p38alpha within lung myofibroblasts is essential for spontaneous fibrosis resolution. J Clin Invest. 2024;134 (10 ).
70 Vaccaro C , Brody JS . Ultrastructure of developing alveoli. I. The role of the interstitial fibroblast. Anat Rec. 1978;192 (4 ):467‐479.736269
71 Schipke J , Kuhlmann S , Hegermann J , et al. Lipofibroblasts in structurally normal, fibrotic, and emphysematous human lungs. Am J Respir Crit Care Med. 2021;204 (2 ):227‐230.34015242
72 El Agha E , Moiseenko A , Kheirollahi V , et al. Two‐way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell. 2017;20 (2 ):261‐273.27867035
73 Zhang Y , Fu J , Li C , et al. Omentin‐1 induces mechanically activated fibroblasts lipogenic differentiation through pkm2/yap/ppargamma pathway to promote lung fibrosis resolution. Cell Mol Life Sci. 2023;80 (10 ):308.37768341
74 Xie T , Wang Y , Deng N , et al. Single‐cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep. 2018;22 (13 ):3625‐3640.29590628
75 Liu X , Rowan SC , Liang J , et al. Categorization of lung mesenchymal cells in development and fibrosis. iScience. 2021;24 (6 ):102551.34151224
76 Castranova V , Rabovsky J , Tucker JH , Miles PR . The alveolar type II epithelial cell: a multifunctional pneumocyte. Toxicol Appl Pharmacol. 1988;93 (3 ):472‐483.3285521
77 Toth A , Kannan P , Snowball J , et al. Alveolar epithelial progenitor cells require Nkx2‐1 to maintain progenitor‐specific epigenomic state during lung homeostasis and regeneration. Nat Commun. 2023;14 (1 ):8452.38114516
78 Barkauskas CE , Cronce MJ , Rackley CR , et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest. 2013;123 (7 ):3025‐3036.23921127
79 Liu K , Meng X , Liu Z , et al. Tracing the origin of alveolar stem cells in lung repair and regeneration. Cell. 2024;187 (10 ):2428‐2445.38579712
80 Zhao F , Wang J , Wang Q , et al. Organoid technology and lung injury mouse models evaluating effects of hydroxychloroquine on lung epithelial regeneration. Exp Anim. 2022;71 (3 ):316‐328.35197405
81 Kobayashi Y , Tata A , Konkimalla A , et al. Persistence of a regeneration‐associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat Cell Biol. 2020;22 (8 ):934‐946.32661339
82 Choi J , Park JE , Tsagkogeorga G , et al. Inflammatory signals induce AT2 cell‐derived damage‐associated transient progenitors that mediate alveolar regeneration. Cell Stem Cell. 2020;27 (3 ):366‐382.32750316
83 Li K , Zhang Q , Li L , et al. DJ‐1 governs airway progenitor cell/eosinophil interactions to promote allergic inflammation. J Allergy Clin Immunol. 2022;150 (5 ):1178‐1193. e13.35724763
84 Fukumoto J , Soundararajan R , Leung J , et al. The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis. Aging (Albany NY). 2016;8 (11 ):3091‐3109.27899769
85 Kumar A , Elko E , Bruno SR , et al. Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis. Thorax. 2022;77 (7 ):669‐678.34400514
86 Chakraborty A , Mastalerz M , Ansari M , Schiller HB , Staab‐Weijnitz CA . Emerging roles of airway epithelial cells in idiopathic pulmonary fibrosis. Cells. 2022;11 (6 ).
87 Park SY , Hong JY , Lee SY , et al. Club cell‐specific role of programmed cell death 5 in pulmonary fibrosis. Nat Commun. 2021;12 (1 ):2923.34011956
88 Ray S , Chiba N , Yao C , et al. Rare SOX2(+) airway progenitor cells generate KRT5(+) cells that repopulate damaged alveolar parenchyma following influenza virus infection. Stem Cell Reports. 2016;7 (5 ):817‐825.27773701
89 Bauer JG . Simplified matrix for Class V amalgam restorations. J Prosthet Dent. 1979;42 (2 ):231‐233.287801
90 Kotton DN , Morrisey EE . Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med. 2014;20 (8 ):822‐832.25100528
91 Hewitt RJ , Puttur F , Gaboriau DCA , et al. Lung extracellular matrix modulates KRT5(+) basal cell activity in pulmonary fibrosis. Nat Commun. 2023;14 (1 ):6039.37758700
92 Zhou Y , Yang Y , Guo L , et al. Airway basal cells show regionally distinct potential to undergo metaplastic differentiation. Elife. 2022:11.
93 Carraro G , Mulay A , Yao C , et al. Single‐cell reconstruction of human basal cell diversity in normal and idiopathic pulmonary fibrosis lungs. Am J Respir Crit Care Med. 2020;202 (11 ):1540‐1550.32692579
94 Heinzelmann K , Hu Q , Hu Y , et al. Single‐cell RNA sequencing identifies G‐protein coupled receptor 87 as a basal cell marker expressed in distal honeycomb cysts in idiopathic pulmonary fibrosis. Eur Respir J. 2022;59 (6 ):2102373.35604813
95 Wu M , Zhang X , Lin Y , Zeng Y . Roles of airway basal stem cells in lung homeostasis and regenerative medicine. Respir Res. 2022;23 (1 ):122.35562719
96 Peng Y , Wang ZN , Xu AR , et al. Mucus hypersecretion and ciliary impairment in conducting airway contribute to alveolar mucus plugging in idiopathic pulmonary fibrosis. Front Cell Dev Biol. 2021;9 :810842.35174169
97 Sari E , He C , Margaroli C . Plasticity towards rigidity: a macrophage conundrum in pulmonary fibrosis. Int J Mol Sci. 2022;23 (19 ):11443.36232756
98 Cheng P , Li S , Chen H . Macrophages in lung injury, repair, and fibrosis. Cells. 2021;10 (2 ):436.33670759
99 Yang G , Yang Y , Liu Y , Liu X . Regulation of alveolar macrophage death in pulmonary fibrosis: a review. Apoptosis. 2023;28 (11‐12 ):1505‐1519.37707713
100 Chakarov S , Lim HY , Tan L , et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science. 2019;363 (6432 ):eaau0964.30872492
101 Misharin AV , Morales‐Nebreda L , Reyfman PA , et al. Monocyte‐derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214 (8 ):2387‐2404.28694385
102 Watson CK , Schloesser D , Fundel‐Clemens K , et al. Antifibrotic drug nintedanib inhibits CSF1R to promote IL‐4‐associated tissue repair macrophages. Am J Respir Cell Mol Biol. 2023;68 (4 ):366‐380.36227799
103 Reyfman PA , Walter JM , Joshi N , et al. Single‐cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. Am J Respir Crit Care Med. 2019;199 (12 ):1517‐1536.30554520
104 Strizova Z , Benesova I , Bartolini R , et al. M1/M2 macrophages and their overlaps—myth or reality?. Clin Sci (Lond). 2023;137 (15 ):1067‐1093.37530555
105 Perrot CY , Karampitsakos T , Herazo‐Maya JD . Monocytes and macrophages: emerging mechanisms and novel therapeutic targets in pulmonary fibrosis. Am J Physiol Cell Physiol. 2023;325 (4 ):C1046‐C1057.37694283
106 Miura S , Iwamoto H , Namba M , et al. High S100A9 level predicts poor survival, and the S100A9 inhibitor paquinimod is a candidate for treating idiopathic pulmonary fibrosis. BMJ Open Respir Res. 2024;11 (1 ):e001803.
107 Yan S , Li M , Liu B , Ma Z , Yang Q . Neutrophil extracellular traps and pulmonary fibrosis: an update. J Inflamm (Lond). 2023;20 (1 ):2.36658568
108 Leslie J , Millar BJ , Del Carpio Pons A , et al. FPR‐1 is an important regulator of neutrophil recruitment and a tissue‐specific driver of pulmonary fibrosis. JCI Insight. 2020;5 (4 ):e125937.32102985
109 Ding L , Yang J , Zhang C , Zhang X , Gao P . Neutrophils modulate fibrogenesis in chronic pulmonary diseases. Front Med (Lausanne). 2021;8 :616200.33987189
110 Mutsaers SE , Miles T , Prele CM , Hoyne GF . Emerging role of immune cells as drivers of pulmonary fibrosis. Pharmacol Ther. 2023;252 :108562.37952904
111 Xu Y , Lan P , Wang T . The role of immune cells in the pathogenesis of idiopathic pulmonary fibrosis. Medicina (Kaunas). 2023;59 (11 ).
112 Serezani APM , Pascoalino BD , Bazzano JMR , et al. Multiplatform single‐cell analysis identifies immune cell types enhanced in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2022;67 (1 ):50‐60.35468042
113 Roman J , Chiba H . B cells in idiopathic pulmonary fibrosis: targeting immune cells with antifibrotic agents. Am J Respir Cell Mol Biol. 2021;64 (6 ):652‐654.33725473
114 Prele CM , Miles T , Pearce DR , et al. Plasma cell but not CD20‐mediated B‐cell depletion protects from bleomycin‐induced lung fibrosis. Eur Respir J. 2022;60 (5 ):2101469.35798357
115 Snyder ME , Anderson MR , Benvenuto LJ , et al. Impact of age and telomere length on circulating T cells and rejection risk after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant. 2023;42 (12 ):1666‐1677.37544465
116 Wang X , Zhang H , Wang Y , et al. DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T‐cell immunity. EMBO J. 2023;42 (8 ):e110597.36912165
117 Kagawa K , Sato S , Koyama K , et al. The lymphocyte‐specific protein tyrosine kinase‐specific inhibitor A‐770041 attenuates lung fibrosis via the suppression of TGF‐beta production in regulatory T‐cells. PLoS One. 2022;17 (10 ):e0275987.36301948
118 Cui G , Shimba A , Jin J , et al. CD45 alleviates airway inflammation and lung fibrosis by limiting expansion and activation of ILC2s. Proc Natl Acad Sci USA. 2023;120 (36 ):e2215941120.37639581
119 Nakatsuka Y , Yaku A , Handa T , et al. Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase‐1. Eur Respir J. 2021;57 (3 ):2000018.32978308
120 Otaki N , Motomura Y , Terooatea T , et al. Activation of ILC2s through constitutive IFNgamma signaling reduction leads to spontaneous pulmonary fibrosis. Nat Commun. 2023;14 (1 ):8120.38097562
121 May J , Mitchell JA , Jenkins RG . Beyond epithelial damage: vascular and endothelial contributions to idiopathic pulmonary fibrosis. J Clin Invest. 2023;133 (18 ):e172058.37712420
122 Wu X , Zhang D , Qiao X , et al. Regulating the cell shift of endothelial cell‐like myofibroblasts in pulmonary fibrosis. Eur Respir J. 2023;61 (6 ):2201799.36758986
123 Yanagihara T , Guignabert C , Kolb MRJ . Endothelial cells in pulmonary fibrosis: more than a bystander. Eur Respir J. 2023;61 (6 ):2300407.37290810
124 Chen Q , Rehman J , Chan M , et al. Angiocrine sphingosine‐1‐phosphate activation of S1PR2‐YAP signaling axis in alveolar type II cells is essential for lung repair. Cell Rep. 2020;31 (13 ):107828.32610129
125 Volpe MC , Ciucci G , Zandomenego G , et al. Flt1 produced by lung endothelial cells impairs ATII cell transdifferentiation and repair in pulmonary fibrosis. Cell Death Dis. 2023;14 (7 ):437.37454154
126 Yanagihara T , Tsubouchi K , Zhou Q , et al. Vascular‐parenchymal cross‐talk promotes lung fibrosis through BMPR2 signaling. Am J Respir Crit Care Med. 2023;207 (11 ):1498‐1514.36917778
127 Li R , Li J , Zhou X . Lung microbiome: new insights into the pathogenesis of respiratory diseases. Signal Transduct Target Ther. 2024;9 (1 ):19.38228603
128 Amati F , Stainer A , Mantero M , et al. Lung microbiome in idiopathic pulmonary fibrosis and other interstitial lung diseases. Int J Mol Sci. 2022;23 (2 ):977.35055163
129 Natalini JG , Singh S , Segal LN . The dynamic lung microbiome in health and disease. Nat Rev Microbiol. 2023;21 (4 ):222‐235.36385637
130 D'Alessandro‐Gabazza CN , Yasuma T , Kobayashi T , et al. Inhibition of lung microbiota‐derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis. Nat Commun. 2022;13 (1 ):1558.35322016
131 Saint‐Criq V , Lugo‐Villarino G , Thomas M . Dysbiosis, malnutrition and enhanced gut‐lung axis contribute to age‐related respiratory diseases. Ageing Res Rev. 2021;66 :101235.33321253
132 Wu Y , Li Y , Luo Y , et al. Gut microbiome and metabolites: the potential key roles in pulmonary fibrosis. Front Microbiol. 2022;13 :943791.36274689
133 Gong GC , Song SR , Su J . Pulmonary fibrosis alters gut microbiota and associated metabolites in mice: an integrated 16S and metabolomics analysis. Life Sci. 2021;264 :118616.33098825
134 Dong Y , He L , Zhu Z , et al. The mechanism of gut‐lung axis in pulmonary fibrosis. Front Cell Infect Microbiol. 2024;14 :1258246.38362497
135 Deng Z , Fan T , Xiao C , et al. TGF‐beta signaling in health, disease, and therapeutics. Signal Transduct Target Ther. 2024;9 (1 ):61.38514615
136 Moss BJ , Ryter SW , Rosas IO . Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annu Rev Pathol. 2022;17 :515‐546.34813355
137 Chen Z , Zhang N , Chu HY , et al. Connective tissue growth factor: from molecular understandings to drug discovery. Front Cell Dev Biol. 2020;8 :593269.33195264
138 Frangogiannis N . Transforming growth factor‐beta in tissue fibrosis. J Exp Med. 2020;217 (3 ):e20190103.32997468
139 Peng D , Fu M , Wang M , Wei Y , Wei X . Targeting TGF‐beta signal transduction for fibrosis and cancer therapy. Mol Cancer. 2022;21 (1 ):104.35461253
140 Shi X , Young CD , Zhou H , Wang X . Transforming growth factor‐beta signaling in fibrotic diseases and cancer‐associated fibroblasts. Biomolecules. 2020;10 (12 ):1666.33322749
141 Wang Q , Xie Z , Wan N , et al. Potential biomarkers for diagnosis and disease evaluation of idiopathic pulmonary fibrosis. Chin Med J (Engl). 2023;136 (11 ):1278‐1290.37130223
142 Kubbara A , Amundson WH , Herman A , Lee AM , Bishop JR , Kim HJ . Genetic variations in idiopathic pulmonary fibrosis and patient response to pirfenidone. Heliyon. 2023;9 (8 ):e18573.37560683
143 Aros CJ , Pantoja CJ , Gomperts BN . Wnt signaling in lung development, regeneration, and disease progression. Commun Biol. 2021;4 (1 ):601.34017045
144 Lv Q , Wang J , Xu C , Huang X , Ruan Z , Dai Y . Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK‐3beta/beta‐catenin and TGF‐beta1/Smad2/3 signaling pathways. Mol Med. 2020;26 (1 ):49.32448163
145 Liu T , Gonzalez De Los Santos F , Hirsch M , Wu Z , Phan SH . Noncanonical Wnt signaling promotes myofibroblast differentiation in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2021;65 (5 ):489‐499.34107237
146 Huang G , Liang J , Huang K , et al. Basal cell‐derived WNT7A promotes fibrogenesis at the fibrotic niche in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2023;68 (3 ):302‐313.36318668
147 Ai JY , Liu CF , Zhang W , Rao GW . Current status of drugs targeting PDGF/PDGFR. Drug Discov Today. 2024;29 (7 ):103989.38663580
148 Noskovicova N , Petrek M , Eickelberg O , Heinzelmann K . Platelet‐derived growth factor signaling in the lung. From lung development and disease to clinical studies. Am J Respir Cell Mol Biol. 2015;52 (3 ):263‐284.25303647
149 Zhao F , Zhang YF , Liu YG , et al. Therapeutic effects of bone marrow‐derived mesenchymal stem cells engraftment on bleomycin‐induced lung injury in rats. Transplant Proc. 2008;40 (5 ):1700‐1705.18589176
150 Walsh J , Absher M , Kelley J . Variable expression of platelet‐derived growth factor family proteins in acute lung injury. Am J Respir Cell Mol Biol. 1993;9 (6 ):637‐644.7504929
151 Shimizu S , Gabazza EC , Taguchi O , et al. Activated protein C inhibits the expression of platelet‐derived growth factor in the lung. Am J Respir Crit Care Med. 2003;167 (10 ):1416‐1426.12738599
152 Glaviano A , Foo ASC , Lam HY , et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22 (1 ):138.37596643
153 Hu X , Xu Q , Wan H , et al. PI3K‐Akt‐mTOR/PFKFB3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide‐induced pulmonary fibrosis. Lab Invest. 2020;100 (6 ):801‐811.32051533
154 Pei X , Zheng F , Li Y , et al. Niclosamide ethanolamine salt alleviates idiopathic pulmonary fibrosis by modulating the PI3K‐mTORC1 pathway. Cells. 2022;11 (3 ):346.35159160
155 Gokey JJ , Patel SD , Kropski JA . The role of Hippo/YAP signaling in alveolar repair and pulmonary fibrosis. Front Med (Lausanne). 2021;8 :752316.34671628
156 Mia MM , Singh MK . New insights into Hippo/YAP signaling in fibrotic diseases. Cells. 2022;11 (13 ):20653.
157 Sun M , Sun Y , Feng Z , et al. New insights into the Hippo/YAP pathway in idiopathic pulmonary fibrosis. Pharmacol Res. 2021;169 :105635.33930530
158 Huang LS , Sudhadevi T , Fu P , et al. Sphingosine kinase 1/S1P signaling contributes to pulmonary fibrosis by activating Hippo/YAP pathway and mitochondrial reactive oxygen species in lung fibroblasts. Int J Mol Sci. 2020;21 (6 ):2064.32192225
159 Du W , Tang Z , Yang F , Liu X , Dong J . Icariin attenuates bleomycin‐induced pulmonary fibrosis by targeting Hippo/YAP pathway. Biomed Pharmacother. 2021;143 :112152.34536758
160 Yan P , Liu J , Li Z , et al. Glycolysis reprogramming in idiopathic pulmonary fibrosis: unveiling the mystery of lactate in the lung. Int J Mol Sci. 2023;25 (1 ):315.38203486
161 Wang Y , Wang X , Du C , et al. Glycolysis and beyond in glucose metabolism: exploring pulmonary fibrosis at the metabolic crossroads. Front Endocrinol (Lausanne). 2024;15 :1379521.38854692
162 Zhou B , Lin W , Long Y , et al. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022;7 (1 ):95.35332121
163 Wang YC , Chen Q , Luo JM , et al. Notch1 promotes the pericyte‐myofibroblast transition in idiopathic pulmonary fibrosis through the PDGFR/ROCK1 signal pathway. Exp Mol Med. 2019;51 (3 ):1‐11.
164 Vera L , Garcia‐Olloqui P , Petri E , et al. Notch3 deficiency attenuates pulmonary fibrosis and impedes lung‐function decline. Am J Respir Cell Mol Biol. 2021;64 (4 ):465‐476.33493092
165 Kato K , Hecker L . NADPH oxidases: pathophysiology and therapeutic potential in age‐associated pulmonary fibrosis. Redox Biol. 2020;33 :101541.32360174
166 Makena P , Kikalova T , Prasad GL , Baxter SA . Oxidative stress and lung fibrosis: towards an adverse outcome pathway. Int J Mol Sci. 2023;24 (15 ):12490.37569865
167 Lee JU , Song KS , Hong J , et al. Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF‐beta1 activity. Exp Mol Med. 2024;56 (2 ):478‐490.38413821
168 Luo J , Li P , Dong M , et al. SLC15A3 plays a crucial role in pulmonary fibrosis by regulating macrophage oxidative stress. Cell Death Differ. 2024;31 (4 ):417‐430.38374230
169 Hill C , Wang Y . Autophagy in pulmonary fibrosis: friend or foe?. Genes Dis. 2022;9 (6 ):1594‐1607.36119644
170 Li X , Wu J , Sun X , et al. Autophagy reprograms alveolar progenitor cell metabolism in response to lung injury. Stem Cell Reports. 2020;14 (3 ):420‐432.32059792
171 Yue YL , Zhang MY , Liu JY , Fang LJ , Qu YQ . The role of autophagy in idiopathic pulmonary fibrosis: from mechanisms to therapies. Ther Adv Respir Dis. 2022;16 :17534666221140972.36468453
172 Ren L , Chang YF , Jiang SH , Li XH , Cheng HP . DNA methylation modification in idiopathic pulmonary fibrosis. Front Cell Dev Biol. 2024;12 :1416325.38915445
173 Korfei M , Mahavadi P , Guenther A . Targeting histone deacetylases in idiopathic pulmonary fibrosis: a future therapeutic option. Cells. 2022;11 (10 ):1626.35626663
174 Qian W , Yang L , Li T , Li W , Zhou J , Xie S . RNA modifications in pulmonary diseases. MedComm. 2024;5 (5 ):e546.38706740
175 Wijsenbeek M , Swigris JJ , Inoue Y , et al. Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis. Eur Respir J. 2024;63 (2 ):230075.
176 Selvarajah B , Plate M , Chambers RC . Pulmonary fibrosis: emerging diagnostic and therapeutic strategies. Mol Aspects Med. 2023;94 :101227.38000335
177 Yoon HY , Lee SH , Ha S , Ryu JS , Song JW . The value of (18)F‐FDG PET/CT in evaluating disease severity and prognosis in idiopathic pulmonary fibrosis patients. J Korean Med Sci. 2021;36 (41 ):e257.34697928
178 Rea G , Sverzellati N , Bocchino M , et al. Beyond visual interpretation: quantitative analysis and artificial intelligence in interstitial lung disease diagnosis “expanding horizons in radiology”. Diagnostics (Basel). 2023;13 (14 ):2333.37510077
179 Capaccione KM , Wang A , Lee SM , et al. Quantifying normal lung in pulmonary fibrosis: cT analysis and correlation with %DLCO. Clin Imaging. 2021;77 :287‐290.34171742
180 Khor YH , Farooqi M , Hambly N , et al. Trajectories and prognostic significance of 6‐minute walk test parameters in fibrotic interstitial lung disease: a multicenter study. Chest. 2023;163 (2 ):345‐357.36089070
181 Hansen AH , Breisnes HW , Prior TS , et al. A serologically assessed neo‐epitope biomarker of cellular fibronectin degradation is related to pulmonary fibrosis. Clin Biochem. 2023;118 :110599.37343745
182 Patel H , Shah JR , Patel DR , Avanthika C , Jhaveri S , Gor K . Idiopathic pulmonary fibrosis: diagnosis, biomarkers and newer treatment protocols. Dis Mon. 2023;69 (7 ):101484.36220705
183 Clynick B , Corte TJ , Jo HE , et al. Biomarker signatures for progressive idiopathic pulmonary fibrosis. Eur Respir J. 2022;59 (3 ):2101181.34675050
184 Khan FA , Stewart I , Saini G , Robinson KA , Jenkins RG . A systematic review of blood biomarkers with individual participant data meta‐analysis of matrix metalloproteinase‐7 in idiopathic pulmonary fibrosis. Eur Respir J. 2022;59 (4 ):2101612.34588192
185 Tang Z , Xia Z , Wang X , Liu Y . The critical role of osteopontin (OPN) in fibrotic diseases. Cytokine Growth Factor Rev. 2023;74 :86‐99.37648616
186 Yamato H , Kimura K , Fukui E , et al. Periostin secreted by activated fibroblasts in idiopathic pulmonary fibrosis promotes tumorigenesis of non‐small cell lung cancer. Sci Rep. 2021;11 (1 ):21114.34702952
187 Chung C , Kim J , Cho HS , Kim HC . Baseline serum Krebs von den Lungen‐6 as a biomarker for the disease progression in idiopathic pulmonary fibrosis. Sci Rep. 2022;12 (1 ):8564.35595812
188 Adegunsoye A , Alqalyoobi S , Linderholm A , et al. Circulating plasma biomarkers of survival in antifibrotic‐treated patients with idiopathic pulmonary fibrosis. Chest. 2020;158 (4 ):1526‐1534.32450241
189 Comes A , Sgalla G , Ielo S , Magri T , Richeldi L . Challenges in the diagnosis of idiopathic pulmonary fibrosis: the importance of a multidisciplinary approach. Expert Rev Respir Med. 2023;17 (4 ):1‐11.
190 Ding D , Luan R , Xue Q , Yang J . Prognostic significance of peripheral blood S100A12, S100A8, and S100A9 concentrations in idiopathic pulmonary fibrosis. Cytokine. 2023;172 :156387.37826869
191 Wu Z , Chen H , Ke S , et al. Identifying potential biomarkers of idiopathic pulmonary fibrosis through machine learning analysis. Sci Rep. 2023;13 (1 ):16559.37783761
192 Shi X , Chen Y , Shi M , et al. The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single‐cell RNA‐seq databases. Lipids Health Dis. 2024;23 (1 ):98.38570797
193 Ruwanpura SM , Thomas BJ , Bardin PG . Pirfenidone: molecular mechanisms and potential clinical applications in lung disease. Am J Respir Cell Mol Biol. 2020;62 (4 ):413‐422.31967851
194 Molina‐Molina M , Shull JG , Vicens‐Zygmunt V , et al. Gastrointestinal pirfenidone adverse events in idiopathic pulmonary fibrosis depending on diet: the MADIET clinical trial. Eur Respir J. 2023;62 (4 ):2300262.37857429
195 Kim JS , Murray S , Yow E , et al. Comparison of pirfenidone and nintedanib: post hoc analysis of the CleanUP‐IPF study. Chest. 2024;165 (5 ):1163‐1173.38030064
196 Inoue Y , Kitamura H , Okamoto M , et al. The effect of nintedanib on health‐related quality of life in Japanese patients with progressive fibrosing interstitial lung diseases: a subset analysis of the INBUILD trial. Respir Investig. 2024;62 (4 ):589‐596.
197 Deterding R , Young LR , DeBoer EM , et al. Nintedanib in children and adolescents with fibrosing interstitial lung diseases. Eur Respir J. 2023;61 (2 ):2201512.36041751
198 Matteson EL , Aringer M , Burmester GR , Mueller H , Moros L , Kolb M . Effect of nintedanib in patients with progressive pulmonary fibrosis associated with rheumatoid arthritis: data from the INBUILD trial. Clin Rheumatol. 2023;42 (9 ):2311‐2319.37209188
199 Cottin V , Richeldi L , Rosas I , et al. Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases. Respir Res. 2021;22 (1 ):84.33726766
200 Inoue Y , Suda T , Kitamura H , et al. Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: subgroup analysis of the randomised, double‐blind, placebo‐controlled, phase 3 INBUILD trial. Respir Med. 2021;187 :106574.34564020
201 Schmid U , Weber B , Sarr C , Freiwald M . Exposure‐safety analyses of nintedanib in patients with chronic fibrosing interstitial lung disease. BMC Pulm Med. 2021;21 (1 ):244.34289823
202 Kuwana M , Ogura T , Makino S , et al. Nintedanib in patients with systemic sclerosis‐associated interstitial lung disease: a Japanese population analysis of the SENSCIS trial. Mod Rheumatol. 2021;31 (1 ):141‐150.32243207
203 Richeldi L , Kolb M , Jouneau S , et al. Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis. BMC Pulm Med. 2020;20 (1 ):3.31914963
204 Wells AU , Flaherty KR , Brown KK , et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases‐subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double‐blind, placebo‐controlled, parallel‐group trial. Lancet Respir Med. 2020;8 (5 ):453‐460.32145830
205 Song JW , Ogura T , Inoue Y , et al. Long‐term treatment with nintedanib in Asian patients with idiopathic pulmonary fibrosis: results from INPULSIS(R)‐ON. Respirology. 2020;25 (4 ):410‐416.31329360
206 Moor CC , Mostard RLM , Grutters JC , et al. Home monitoring in patients with idiopathic pulmonary fibrosis. A randomized controlled trial. Am J Respir Crit Care Med. 2020;202 (3 ):393‐401.32325005
207 Lamb YN . Nintedanib: a review in fibrotic interstitial lung diseases. Drugs. 2021;81 (5 ):575‐586.33765296
208 Flaherty KR , Wells AU , Cottin V , et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381 (18 ):1718‐1727.31566307
209 Solomon JJ , Danoff SK , Woodhead FA , et al. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis‐associated interstitial lung disease: a randomised, double‐blind, placebo‐controlled, phase 2 study. Lancet Respir Med. 2023;11 (1 ):87‐96.36075242
210 Behr J , Prasse A , Kreuter M , et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double‐blind, randomised, placebo‐controlled, phase 2b trial. Lancet Respir Med. 2021;9 (5 ):476‐486.33798455
211 Kreuter M , Maher TM , Corte TJ , et al. Pirfenidone in unclassifiable interstitial lung disease: a subgroup analysis by concomitant mycophenolate mofetil and/or previous corticosteroid use. Adv Ther. 2022;39 (2 ):1081‐1095.34936057
212 Sakamoto S , Kataoka K , Kondoh Y , et al. Pirfenidone plus inhaled N‐acetylcysteine for idiopathic pulmonary fibrosis: a randomised trial. Eur Respir J. 2021;57 (1 ):2000348.32703779
213 Behr J , Nathan SD , Wuyts WA , et al. Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double‐blind, randomised, placebo‐controlled, phase 2b trial. Lancet Respir Med. 2021;9 (1 ):85‐95.32822614
214 Blackwell TS , Hewlett JC , Mason WR , et al. A phase I randomized, controlled, clinical trial of valganciclovir in idiopathic pulmonary fibrosis. Ann Am Thorac Soc. 2021;18 (8 ):1291‐1297.33740394
215 Maher TM , Corte TJ , Fischer A , et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double‐blind, randomised, placebo‐controlled, phase 2 trial. Lancet Respir Med. 2020;8 (2 ):147‐157.31578169
216 Ikeda K , Chiba H , Nishikiori H , et al. Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post‐hoc analysis of the phase 3 trial in Japan. Respir Res. 2020;21 (1 ):316.33256760
217 Rajan SK , Cottin V , Dhar R , et al. Progressive pulmonary fibrosis: an expert group consensus statement. Eur Respir J. 2023;61 (3 ):2103187.36517177
218 Miozzo AP , Watte G , Hetzel GM , et al. Ambulatory oxygen therapy in lung transplantation candidates with idiopathic pulmonary fibrosis referred for pulmonary rehabilitation. J Bras Pneumol. 2023;49 (2 ):e20220280.36820744
219 Sanguanwong N , Jantarangsi N , Ngeyvijit J , Owattanapanich N , Phoophiboon V . Effect of noninvasive respiratory support on interstitial lung disease with acute respiratory failure: a systematic review and meta‐analysis. Can J Respir Ther. 2023;59 :232‐244.37933263
220 Le Pavec J , Dauriat G , Gazengel P , et al. Lung transplantation for idiopathic pulmonary fibrosis. Presse Med. 2020;49 (2 ):104026.32437844
221 She YX , Yu QY , Tang XX . Role of interleukins in the pathogenesis of pulmonary fibrosis. Cell Death Discov. 2021;7 (1 ):52.33723241
222 Jiang A , Liu N , Wang J , et al. The role of PD‐1/PD‐L1 axis in idiopathic pulmonary fibrosis: friend or foe?. Front Immunol. 2022;13 :1022228.36544757
223 Zhou BW , Liu HM , Xu F , Jia XH . The role of macrophage polarization and cellular crosstalk in the pulmonary fibrotic microenvironment: a review. Cell Commun Signal. 2024;22 (1 ):172.38461312
224 Deng L , Huang T , Zhang L . T cells in idiopathic pulmonary fibrosis: crucial but controversial. Cell Death Discov. 2023;9 (1 ):62.36788232
225 Jandl K , Radic N , Zeder K , Kovacs G , Kwapiszewska G . Pulmonary vascular fibrosis in pulmonary hypertension—The role of the extracellular matrix as a therapeutic target. Pharmacol Ther. 2023;247 :108438.37210005
226 Richeldi L , Fernandez Perez ER , Costabel U , et al. Pamrevlumab, an anti‐connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double‐blind, placebo‐controlled trial. Lancet Respir Med. 2020;8 (1 ):25‐33.31575509
227 Ding H , Cui Y , Yang J , et al. ROS‐responsive microneedles loaded with integrin avbeta6‐blocking antibodies for the treatment of pulmonary fibrosis. J Control Release. 2023;360 :365‐375.37331606
228 Mendoza FA , Jimenez SA . Serine/threonine kinase inhibition as antifibrotic therapy: transforming growth factor‐beta and Rho kinase inhibitors. Rheumatology (Oxford). 2022;61 (4 ):1354‐1365.34664623
229 Higo H , Ohashi K , Tomida S , et al. Identification of targetable kinases in idiopathic pulmonary fibrosis. Respir Res. 2022;23 (1 ):20.35130915
230 Chulia‐Peris L , Carreres‐Rey C , Gabasa M , Alcaraz J , Carretero J , Pereda J . Matrix metalloproteinases and their inhibitors in pulmonary fibrosis: EMMPRIN/CD147 comes into play. Int J Mol Sci. 2022;23 (13 ):6894.35805895
231 Revert‐Ros F , Ventura I , Prieto‐Ruiz JA , Hernandez‐Andreu JM , Revert F . The versatility of collagen in pharmacology: targeting collagen, targeting with collagen. Int J Mol Sci. 2024;25 (12 ):6523.38928229
232 Merkt W , Bueno M , Mora AL , Lagares D . Senotherapeutics: targeting senescence in idiopathic pulmonary fibrosis. Semin Cell Dev Biol. 2020;101 :104‐110.31879264
233 Zhou Q , Yi G , Chang M , et al. Activation of Sirtuin3 by honokiol ameliorates alveolar epithelial cell senescence in experimental silicosis via the cGAS‐STING pathway. Redox Biol. 2024;74 :103224.38865904
234 Rehan M , Kurundkar D , Kurundkar AR , et al. Restoration of SIRT3 gene expression by airway delivery resolves age‐associated persistent lung fibrosis in mice. Nat Aging. 2021;1 (2 ):205‐217.34386777
235 Guan R , Yuan L , Li J , et al. Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts. Eur Respir J. 2022;60 (6 ):2102307.35777761
236 Huang T , Lin R , Su Y , et al. Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis. Nat Commun. 2023;14 (1 ):5781.37723135
237 Chung KP , Hsu CL , Fan LC , et al. Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis. Nat Commun. 2019;10 (1 ):3390.31358769
238 Lu Y , Mu M , RenChen X , et al. 2‐Deoxy‐D‐glucose ameliorates inflammation and fibrosis in a silicosis mouse model by inhibiting hypoxia‐inducible factor‐1alpha in alveolar macrophages. Ecotoxicol Environ Saf. 2024;269 :115767.38039851
239 Li J , Zhai X , Sun X , Cao S , Yuan Q , Wang J . Metabolic reprogramming of pulmonary fibrosis. Front Pharmacol. 2022;13 :1031890.36452229
240 Huang T , Zhang T , Jiang X , et al. Iron oxide nanoparticles augment the intercellular mitochondrial transfer‐mediated therapy. Sci Adv. 2021;7 (40 ):eabj0534.34586849
241 Larson‐Casey JL , He C , Carter AB . Mitochondrial quality control in pulmonary fibrosis. Redox Biol. 2020;33 :101426.31928788
242 Kleele T , Rey T , Winter J , et al. Distinct fission signatures predict mitochondrial degradation or biogenesis. Nature. 2021;593 (7859 ):435‐439.33953403
243 Zhang W , Wang Y , Du Y , et al. Efficacy of alveolar type II epithelial cell transplantation for pulmonary fibrosis: a meta‐analysis. Iran J Public Health. 2023;52 (1 ):1‐9.36824257
244 Long Y , Yang B , Lei Q , et al. Targeting senescent alveolar epithelial cells using engineered mesenchymal stem cell‐derived extracellular vesicles to treat pulmonary fibrosis. ACS Nano. 2024;18 (9 ):7046‐7063.38381372
245 Lai X , Huang S , Lin S , et al. Mesenchymal stromal cells attenuate alveolar type 2 cells senescence through regulating NAMPT‐mediated NAD metabolism. Stem Cell Res Ther. 2022;13 (1 ):12.35012648
246 Shi C , Chen X , Yin W , Sun Z , Hou J , Han X . Wnt8b regulates myofibroblast differentiation of lung‐resident mesenchymal stem cells via the activation of Wnt/beta‐catenin signaling in pulmonary fibrogenesis. Differentiation. 2022;125 :35‐44.35487030
247 Cheng W , Fan C , Song Q , et al. Induced pluripotent stem cell‐based therapies for organ fibrosis. Front Bioeng Biotechnol. 2023;11 :1119606.37274156
248 Shi Y , Dong M , Zhou Y , et al. Distal airway stem cells ameliorate bleomycin‐induced pulmonary fibrosis in mice. Stem Cell Res Ther. 2019;10 (1 ):161.31159891
249 Bhattacharyya A , Khan R , Lee JY , et al. Gene therapy with AAV9‐SGPL1 in an animal model of lung fibrosis. J Pathol. 2024;263 (1 ):22‐31.38332723
250 Bao R , Wang Q , Yu M , et al. AAV9‐HGF cooperating with TGF‐beta/Smad inhibitor attenuates silicosis fibrosis via inhibiting ferroptosis. Biomed Pharmacother. 2023;161 :114537.36933378
251 Yan L , Hou C , Liu J , et al. Local administration of liposomal‐based Plekhf1 gene therapy attenuates pulmonary fibrosis by modulating macrophage polarization. Sci China Life Sci. 2023;66 (11 ):2571‐2586.37340175
252 Ding L , Tang S , Tang W , et al. Perfluorocarbon nanoemulsions enhance therapeutic siRNA delivery in the treatment of pulmonary fibrosis. Adv Sci (Weinh). 2022;9 (8 ):e2103676.34994102
253 Li Y , Qin W , Liang Q , et al. Bufei huoxue capsule alleviates bleomycin‐induced pulmonary fibrosis in mice via TGF‐beta1/Smad2/3 signaling. J Ethnopharmacol. 2023;316 :116733.37277082
254 Wang Q , Li W , Hu H , Lu X , Qin S . Monomeric compounds from traditional Chinese medicine: new hopes for drug discovery in pulmonary fibrosis. Biomed Pharmacother. 2023;159 :114226.36657302
255 Zhang Y , Lu P , Qin H , et al. Traditional Chinese medicine combined with pulmonary drug delivery system and idiopathic pulmonary fibrosis: rationale and therapeutic potential. Biomed Pharmacother. 2021;133 :111072.33378971
