
==== Front
Biol Direct
Biol Direct
Biology Direct
1745-6150
BioMed Central London

530
10.1186/s13062-024-00530-w
Review
Regulating ferroptosis by non-coding RNAs in hepatocellular carcinoma
Sun Lijie 215029196@qq.com

1
Cao Hongfei chf11310@126.com

1
Wang Yanzhe 1
Wang Hongquan 2
1 https://ror.org/05wr48765 grid.443353.6 0000 0004 1798 8916 Department of Gastroenterology, The Affiliated Hospital of Chifeng University, Chifeng, 024005 China
2 grid.11135.37 0000 0001 2256 9319 Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049 China
12 9 2024
12 9 2024
2024
19 808 8 2024
5 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Ferroptosis, a unique type of regulated cell death plays a vital role in inhibiting tumour malignancy and has presented new opportunities for treatment of therapy in hepatocellular carcinoma. Accumulating studies indicate that epigenetic modifications by non-coding RNAs, including microRNAs, long noncoding RNAs, and circular RNAs, can determine cancer cell vulnerability to ferroptosis in HCC. The present review first summarize the updated core molecular mechanisms of ferroptosis. We then provide a concised overview of epigenetic modification of ferroptosis in HCC. Finally, we review the recent progress in understanding of the ncRNA-mediated regulated mechanisms on ferroptosis in HCC. The review will promote our understanding of the ncRNA-mediated epigenetic regulatory mechanisms modulating ferroptosis in malignancy of HCC, highlighting a novel strategies for treatment of HCC through targeting ncRNA-ferroptosis axis.

Keywords

Hepatocellular carcinoma
Ferroptosis
Non-coding RNAs
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Cancer is ranked as the second leading cause of mortality after cardiovascular diseases worldwide [1]. In 2020 approximately twenty million new cancer cases were diagnosed. Lung, prostate, liver, colorectal, and stomach cancers are the most common cancers among men [2]. Primary liver cancer is the third-leading cause of mortality induced by cancer worldwide and remains a global health challenge [3–5]. The incidence is growing and about one million individuals will develop liver cancer annually by 2025 [4]. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting for ~ 90% of all cases [3, 4].

Although hepatitis B or C virus (HBV or HCV) infection, alcohol-associated liver disease remain important risk factors, metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly becoming a dominant cause of HCC [4, 6–9]. Surgical resection, radiation, and percutaneous ablation, as well as transarterial and systemic therapies are usually used in HCC treatment [6]. Currently, systemic therapies, including molecular targeted therapies using tyrosine kinase inhibitors (TKIs), immune checkpoint blockade therapies and monoclonal antibodies therapies, have challenged the use of conventional therapies for HCC [4, 10]. Molecular targeted therapies have formed the mainstay of systemic therapies against advanced HCC [11]. Unfortunately, drug resistance or therapeutic resistance continues to be a major problem facing current HCC research and the principal limiting factor to achieving cures in patients with HCC [12, 13]. Therefore, it is desirable to elucidat the novel mechanisms underlying HCC and hunting for effective strategies have long been unmet urgent need in cancer treatment [14–16].

Ferroptosis, named as a form of regulated cell death (RCD) induced by iron, is triggered by the toxic build-up of lipid peroxides on cellular membranes [17]. Conventional therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted cancer therapies, mediate the tumour killing effects through inducing ferroptosis [17–21]. Therefore, ferroptosis holds great potential for cancer therapy and targeting ferroptosis might provide new therapeutic opportunities in treating cancers that are resistant to conventional therapies, including HCC among other cancers [22–32]. Therefore, delineating the molecular complexities of regulating ferroptosis in HCC may provide novel insights to create more effective therapeutic strategies in HCC.

Non-coding RNAs (ncRNAs) are functional transcripts having no or limited protein-coding potential [33]. ncRNAs are being increasingly recognized as vital epigenetic modification regulator on ferroptosis [34–40]. Emerging evidences have revealed that ncRNAs modulate ferroptosis and tumour malignancy in HCC. However, the machinery underlying ncRNAs-mediated epigenetic modification of ferroptosis HCC is still to be clarified. Here we first attempt to summarize the updated core molecular mechanisms of ferroptosis. We then provide a concised overview of epigenetic modification of ferroptosis in HCC. Finally, we review the recent progress in understanding of the ncRNA-mediated regulated mechanisms on ferroptosis in HCC. The review will promote our understanding of the ncRNA-mediated epigenetic regulatory mechanisms modulating ferroptosis in malignancy of HCC, highlighting a novel strategies for treatment of HCC through targeting ncRNA-ferroptosis axis.

Core mechanism of ferroptosis

Ferroptosis is named and identified as a novel form of regulated cell death (RCD) driven by lipid peroxidation (LPO) dependent of iron in 2012 [23, 25, 41–44] (Fig. 1). Ferroptosis was first described as a non-apoptotic form of RCD characterized by iron-dependent LPO glutathione (GSH) depletion, and injuried cystine uptake into cells [23]. The research to study the effects of lethal small molecules that induce cell death facilitate the identification of ferroptosis in cancer. Then the following research recognized and identified specific small-molecule ferroptosis inhibitors, which results in revealing the nature of ferroptosis mechanism [45]. The initiation and induction of ferroptosis is involved in three essential elements, i.e. oxidizable lipids, reactive oxygen species (ROS) and LPO [22] (Fig. 2). The imbalance between ferroptosis defense systems and promoting factors facilitates lethal lipid peroxides (technically, lipid hydroperoxides) accumulating on cellular membranes to cause membrane rupture and ensued cell death [17, 46–48].Fig. 1 Key milestones in ferroptosis research

Fig. 2 Core mechanisms of ferroptosis

Ferroptosis prerequisites

The mitochondrial metabolism, iron metabolism, and synthesis and peroxidation of polyunsaturated fatty acids-containing phospholipids (PUFA-PLs) constitute the main prerequisites that trigger and induce ferroptosis [17, 49–51].

Iron-dependant LPO

The ferroptosis is executed by phospholipid peroxidation, a process relying on the PUFA-PLs, transition metal iron and ROS [23, 52, 53]. The peroxidation of PUFA-PLs and the accumulation of peroxidized lipids trigger ferroptosis [48, 54]. The iron chelation emphasize the intricate interplay between lipids and iron, revealing a clear link between iron and ferroptosis [52, 53, 55]. PUFA-PLs are susceptible to peroxidation makes it be the substrates for LPO [47]. During ferroptosis, PUFA-PLs perform LPO through both enzymatic and non-enzymatic mechanisms [47]. The distinct steps of initiation, propagation, and termination constitute the underlying mechanism PUFA-PLs do LPO [56, 57]. The incorporation of the formation of PUFAs peroxides into membrane phospholipids is believed to trigger ferroptosis [58, 59]. Acyl-coenzyme A synthetase long chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) contributes to synthesize the PUFA-PLs. The lipoxygenase (LOX) enzymes (particularly 12/15-LOX i.e., ALOX15), NADPH oxidase (NOX) enzymes, oxidoreductases cytochrome P450 reductase (POR), and NADH-cytochrome b5 reductase (CYB5R1) are the metabolism enzymes can generate oxidants that initiate and induce LPO [60–67]. Mitochondria are the sites substantially generate ROS, which contributes to initiate LPO that drives ferroptosis [51, 68]. The iron and lipids interaction results in LPO, producing lipid peroxides, or PUFA-PLs hydroperoxides or peroxidated PUFA-PLs (PUFA-PL-OOH) and derivatives such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) [48].

Iron in ferroptosis

Iron drive LPO to induce ferroptosis via two mechanisms, i.e. mediates the non-enzymatic Fenton reaction (i.e. the nonenzymatic LPO pathway) and acts as an essential cofactor for these iron-dependent peroxidases including ALOXs and POR (i.e. the enzymatic LPO pathway), which promote LPO, and metabolism in mitochondron enhances the production of ATP, ROS and/or PUFA-PLs [17, 54, 69, 70]. Iron exists in two oxidation states, i.e. ferric iron (Fe3+) and ferrous iron (Fe2+) [71]. Fe2+ reacts with PUFA-PL-OOH to produce hydroxyl radicals that react with PUFAs to propagate LPO [71].

In the nonenzymatic LPO pathway, iron induces ferroptosis by initiating direct peroxidation of PUFA-PLs through non-enzymatic Fenton reaction [57]. Fenton reactions catalyzes and converts hydrogen peroxide (H2O2) to a highly mobile water-soluble form of ROS, hydroxyl radical (HO•). In this nonenzymatic LPO pathway, PUFA-PLs can react with ROS including LO• or HO• through the Fenton reaction to produce PUFA-PL-OOH, thereby triggering LPO [72–74]. PUFA-PL-OOH can propagate peroxidation to neighboring PUFA-PL in the presence of labile iron when it is not quickly enough neutralized. Therefore, cellular processes that can increase the labile iron pool (LIP) in cell, such as inhibition of iron exporter ferroportin [75–77], autophagic degradation of ferritin [78, 79], or uptake of transferrin [80] can increase sensitivity of the cell to ferroptosis [54].

In enzymatic LPO pathway, Fe2+ functions as an essential cofactor for iron-dependent peroxidases to enhance their activity, initiating the dioxygenation of PUFA-PLs in membrane [81, 82]. In this pathway, ACSL4 catalyses and ligates free PUFAs with CoA to produce PUFA-CoAs. Subsequently LPCAT3 re-esterifies and incorporates PUFA-CoAs into PLs [58, 59, 83]. Then the PORs and ALOXs peroxidate the incorporated PUFA-PLs to produce PUFA-PLs-OOH under the help of labile iron and O2 [47, 62, 66]. More recent excellent review have discuss the details of lipid resources in ferroptosis [22, 57, 84].

Ferroptosis defense mechanisms

Normally, the specific surveillance or protection mechanisms need to inhibit LPO to suppress unwanted ferroptosis [70]. Working as the ferroptosis defense systems that directly neutralize lipid peroxides, the cellular antioxidant systems constitute the specific surveillance mechanisms. These ferroptosis defense systems consist of GPX4-dependent or GPX4-independent ferroptosis surveillance pathways with specific subcellular localizations [41].

SLC7A11-GSH-GPX4 axis

SLC7A11-GSH-GPX4 axis is the first identified well-defined ferroptosis defense system [17, 85]. GPX4 is a lipid repair enzyme [86, 87], convert and reduce reactive PUFA-PL-OOH to non-lethal and non-reactive PUFA phospholipid alcohols (PUFA-PL-OH), concomitantly oxidizing two reduced GSH into an oxidized glutathione (GSSG) [88, 89]. Belonging to the GPX protein family, GPX4 works as a key ferroptosis inhibitor through preventing accumulation of lipid hydroperoxide in most cells [23, 90–93]. GPX4 has mitochondrial, nuclear and cytosolic three isoforms with distinctive subcellular localizations. Both cytosolic and mitochondrial GPX4 are vital to suppress ferroptosis in different subcellular compartments [45]. GPX4 functions closely with the cystine/glutamate antiporter System Xc−, which consists of SLC7A11 (also named as xCT) and SLC3A2 (solute carrier family 3 member 2) [53]. xCT functions as the transporter subunit of system Xc− to import extracellular cystine and export intracellular glutamate to biosynthesize reduced GSH [94, 95].

FSP1-CoQH2 system

The ferroptosis suppressor protein 1 (FSP1)-ubiquinone (coenzyme Q10 or CoQ10) system was identified as second endogenous ferroptosis defense system to suppress ferroptosis. The the plasma membrane localized FSP1 GPX4-independently inhibits ferroptosis. Functioning as an NADPH-dependent CoQ reductase, FSP1 converts CoQ10 to its reduced form, ubiquinol (CoQH2), which works as a lipid-soluble antioxidant to prevent LPO and suppress ferroptosis in cellular membranes [96–98]. Meanwhile, FSP1 suppress ferroptosis by repairing plasma membrane damage via activation of ESCRT-III(endosomal sorting complex required for transport III) complex [99, 100].

GCH1-BH4 system

The GTP cyclohydrolase 1(GCH1)-tetrahydrobiopterin (BH4) axis was identified as the second GPX4-independent ferroptosis defense system through inhibiting LPO [101, 102]. BH4 is a endogenous metabolite and radical-trapping antioxidant. GCH1 suppresses ferroptosis through generating BH4 or causing remodeling of the lipid membrane environment, i.e. increasing abundance of reduced CoQ10, and depleting PUFA-PLs that drive sensitivity to ferroptosis [25]. GCH1-mediated generation of BH4 works as a cofactor for aromatic amino acid hydroxylases and analogously to CoQ10 to prevent LPO [101, 102].

DHODH-CoQH2 system

The dihydroorotate dehydrogenase (DHODH)-dihydroubiquione (CoQH2) axis was identified as a third GPX4-independent ferroptosis defense system with mitochondria-localization for inhibiting LPO [103]. As a mitochondrial enzyme located in the inner mitochondrial membrane, DHODH promotes pyrimidine biosynthesis and converts CoQ10 to CoQH2, thereby reducing mitochondrial CoQ10, analogously to FSP1 functioning in the extramitochondrial membranes [103]. After GPX4 is acutely inactivated, increased flux mediated by DHODH enhances production of CoQH2 to neutralizes LPOs, thereby inhibiting mitochondria-derived ferroptosis [103].

MBOAT1/2-MUFA system

A newly GPX4- and FSP1-independent ferroptosis defense system consist of O-acyltransferase domain containing 1/2 (MBOAT1/2)-phosphatidylethanolamine (PE)-monounsaturated fatty acids (MUFA) was identified by Jiang and colleagues in 2023 [104]. The MBOAT1 and MBOAT2 function as inhibitor of ferroptosis in this ferroptosis defense system [104]. The preferred substrate for LPO, PE-PUFA dictates sensitivity of cell to ferroptosis [58, 59]. Working as the lyso-PL acyltransferase (LPLAT), the membrane bound MBOAT2 selectively transfer MUFAs into lyso-phosphatidylethanolamine (lyso-PE), leading to increase cellular PE-MUFA and decrease cellular PE-PUFA, thereby preventing ferroptosis induction. MBOAT1 and MBOAT2 are directly transcriptionally regulated by estrogen receptor (ER) and androgen receptor (AR), respectively [104].

SC5D-7-DHC axis

The ferroptosis defense system consist of lathosterol oxidase (SC5D)-7-dehydrocholesterol (7-DHC) axis was a newly identified ferroptosis inhibitor by two groups in 2024, which reported that 7-DHC works as a natural ferroptosis inhibitor [105, 106]. Generating in the endoplasmic reticulum, 7-DHC is found on the mitochondria and cell membrane in the cholesterol synthesis pathway. 7-DHC diverts the peroxidation pathway from phospholipids and traps radicals to prevent LPO, therebyinhibiting ferroptosis both in the plasma membrane and mitochondria.

ncRNAs-mediated epigenetic modification of ferroptosis in HCC

Epigenetic modification is a dynamic and reversible process to regulate gene expression without changing the DNA sequence [107, 108]. There exist four major mechanisms of epigenetic modification, i.e. chromatin structure regulation, DNA methylation, histone posttranslational modifications (PTMs), and ncRNA regulation [107–109]. The common well-studied epigenetic regulatory mechanisms are DNA methylation, histone modification, and ncRNA regulation [110]. Increasing evidence have shown that dysregulation of epigenetic modifications induce onset and progression of disease through aberrant gene expression, protein signatures and transformation into malignant phenotypes [111–113]. ncRNAs are being increasingly recognized as vital regulatory mediators of ferroptosis. Emerging evidence indicates that epigenetic modification affects ferroptosis at gene transcription, posttranscription, or posttranslation level. Targeting epigenetic and post-translational modifications modulating ferroptosis is thought to offer a new direction for cancers treatment [44, 114]. Recently, ncRNAs have been shown to regulate biological processes of ferroptosis via modulating iron metabolism, mitochondrial-related proteins, glutathione metabolism, and LPO, thus affecting cancer biology [34–40]. In cancer, the mechanisms underlying ncRNAs regulate ferroptosis is ncRNAs regulate ferroptosis-related genes that functions as ferroptosis defense systems or ferroptosis-promoting factors [37]. ncRNAs regulate ferroptosis in cancer cells by affecting iron metabolism, lipid metabolism, SLC7A11/GSH/GPX4 network, glutamine metabolism, KEAP1/Nrf2 pathway among others [37].

The regulatory role of miRNAs in modulation of ferroptosis in HCC

The activating transcription factor 4 (ATF4) inhibits ferroptosis in cancer through enhancing HSPA5-mediated GPX4 protein stability [125] or upregulating SLC7A11 [126] (Table 1 and Fig. 3). miRNA-214-3p facilitates erastin-induced ferroptosis through inhibiting ATF4 in HCC [115]. Overexpression of miRNA-214-3p downregulates HSPA5, however this study did not show whether miRNA-214-3p regulates GPX4 through inhibiting HSPA5 [115]. ETS Proto-Oncogene 1 (ETS1)-mediated upregulated miR-23a-3p was observed in patients whit sorafenib resistance and correlated to poor prognosis [116]. Loss of miR-23a-3p increases sensitivity of HCC cells and orthotopic HCC tumours to sorafenib. miR-23a-3p suppresses sorafenib-induced ferroptosis through inhibiting ACSL4. The miR-23a-3p inhibitor induces ferroptosis through rescuing ACSL4 expression in sorafenib-induced HCC cells. The combined miR-23a-3p inhibitor and ACSL4 siRNA abolishes response to sorafenib [116]. Together, these results suggest that ETS1-dependant miR-23a-3p upregulation leads to sorafenib resistance through inhibiting ferroptosis via suppression of ACSL4 axis, highlighting targeting miR-23a-3p as a potential target to overcome resistance to sorafenib in HCC patients. miR-552-5p inhibits ferroptosis by suppressing ACSL4 in HCC [117]. Overexpression of ZNF8 reduces intracellular miR-552-5p levels and enhances sensitivity to ferroptosis [117].Table 1 The regulatory role of miRNAs in modulation of ferroptosis in HCC

miRNA	Expression/function	Targets	Effects on tumour	Refs.	
miR-214-3p	ND/Tumor suppressor	ATF4	Induce ferroptosis and inhibit HCC	[115]	
miR-23a-3p	↑/Oncogene	ACSL4	miR-23a-3p suppresses sorafenib-induced ferroptosis	[116]	
miR-552-5p	↑/Oncogene	ACSL4	Overexpression of ZNF8 reduces intracellular miR-552-5p levels and enhances sensitivity to ferroptosis. miR-552-5p inhibits ferroptosis by suppressing ACSL4	[117]	
miR-142-3p	↑/Oncogene	FTH1, TfR1, GPX4, ATF4	Exosomal miR-142-3p from HBV-positive liver cancer cell promotes the progression of liver cancer by inducing ferroptosis of M1-type macrophages inhibiting SLC3A2	[118]	
miR-142-3p	↑/Oncogene	SLC3A2	↑HBV-infected M1-type macrophage ferroptosis through inhibiting SLC3A2;↑ development of HCC	[119]	
miR-21-5p	↑/Oncogene	MELK	miR-21-5p inhibits the ferroptosis through activating AKT/mTOR signaling pathway via upregulating level of MELK	[120]	
miR-654-5p	-/Tumor suppressor	HSPB1	miR-654-5p alleviate sorafenib resistance through inducing ferroptosis by targeting HSPB1	[121]	
miR-612	-/Tumor suppressor	CoQ10	miR-612 inhibit tumour malignancy through inducing ferroptosis by decreasing CoQ10 and increasing cellular PUFA levels via the HADHA-mediated MVA pathway	[122]	
MiR-339-5p	↑/Oncogene	FTH1	miR-339 inhibits ferroptosis through suppressing ATG7-mediated autophagic degradation of FTH1	[123]	
miR-4489	-/Tumor suppressor	MUC1	APOM suppress tumor and induces ferroptosis through down-regulating ferroptosis-inhibiting gene MUC1 via upregulating miR-4489	[124]	

Fig. 3 miRNA regulation of ferroptosis in HCC. miRNAs may modify phospholipid metabolism, inhibit antiferroptotic safety measures, or directly induce ferroptosis by modifying cellular redox cycles. Cumulatively, miRNAs play a strong role in maintaining peroxyphospholipid homeostasis

Increased expression of miR-142-3p was observed in the exosomes from the peripheral blood of patients with HBV-positive liver cancer. HBV-positive exosomes induce M1 macrophages ferroptosis, evidenced by increased expression of transferrin receptor 1 (TfR1), and decreased expression of GPX4, FTH1, and ATF4 [118]. HBV-positive HCC exosomes weakens M1-type macrophages-mediated inhibition on the HCC cells invasion, which was reversed by ferroptosis inhibitors. Exosomal miR-142-3p promotes M1 macrophages ferroptosis through inhibiting SLC3A2. Silencing miR-142-3p weaken the invasive ability of liver cancer cells [118]. Together, these results suggest that exosomal miR-142-3p from HBV-positive liver cancer cell promote tumour malignancy by inducing M1-type macrophages ferroptosis through inhibiting SLC3A2 [118]. These results were corroborated by the studies from the same group, which reported exosomal miR-142-3p promoted HBV-infected M1-type macrophage ferroptosis through SLC3A2 [119].

Increased expression of miR-21-5p and MELK, a cell cycle regulator that is involved in tumor growth stem cell turnover, tumor growth, and resistance to chemotherapy was observed in HCC [120]. Overexpression of miR-21-5p and MELK promote tumour malignancy in HCC cells. Silencing miR-21-5p inhibits tumour malignancy and the expression of MELK. MELK inhibits ferroptosis through activating AKT/mTOR signaling pathway. Ferroptosis inducer erastin reverses miR-21-5p-mediated inhibition of ferroptosis and the EMT. Together, these results suggest miR-21-5p inhibits the ferroptosis through activating AKT/mTOR signaling pathway via upregulating level of MELK [120]. Increased heat shock protein family B (small) member 1 (HSPB1) was observed in HCC cells with sorafenib resistance. HSPB1 upregulation-mediated ferroptosis resistance leads to resistance to sorafenib [121]. miR-654-5p facilitates sorafenib-induced ferroptosis through binding to reduce HSPB1 protein levels. miR-654-5p delivered by engineered extracellular vesicles (sEV) to HCC cells increases sorafenib-induced ferroptosis through inhibiting HSPB1 and restoring their sensitivity to sorafenib in HCC cells and xenograft tumors with sorafenib resistance [121]. miR-654-5p alleviates sorafenib resistance through promoting ferroptosis via inhibiting HSPB1 [121].

HCC cells with high metastatic potential show ferroptosis resistance. miR-612 overexpression increases sensitivity of HCC cell to ferroptosis through increasing lipid ROS levels. miR-612 inhibit HCC cells proliferation and metastasis through promoting ferroptosis via downregulating HADHA [122]. HADHA upregulate the expression of key mevalonate (MVA) pathway enzymes. Overexpression of HADHA upregulates the expression of CoQ10 and reduces PUFA levels and lipid peroxide abundance. Together, these results suggest miR-612 could inhibit tumour malignancy through inducing ferroptosis by decreasing CoQ10 via the HADHA-mediated MVA pathway [122]. Increased expression of miR-339 was observed in HCC [123]. Silencing miR-339 inhibits liver cancer progression and induces ferroptosis through activating ATG7-mediated autophagic degradation of FTH1. miR-339 functions as a ferroptosis inhibitor through suppressing ATG7-mediated autophagic degradation of FTH1 [123]. The apolipoprotein M (ApoM) promotes ferroptosis in HCC cells. The MUC1 gene prevents APOM upregulation-mediated ferroptosis. miR-4489 inhibits expression of MUC1. Together, these results suggest that ApoM suppresses tumor and induces ferroptosis through down-regulating cell surface associated ferroptosis-inhibiting gene Mucin 1 (MUC1) via upregulating miR-4489 [124].

The regulatory role of LncRNAs in modulating ferroptosis in HCC

Targeting SLC7A11

Upregulated expression of lncRNA DUXAP8 was observed in liver cancer and correlated with poor prognosis [127] (Table 2 and Fig. 4). LncRNA DUXAP8 decreases the sensitivity of HCC to sorafenib-mediated ferroptosis by increasing SLC7A11, resulting in sorafenib resistance. LncRNA DUXAP8 inhibit lysosome-mediated degradation of SLC7A11 through promoting its palmitoylation, thereby enhancing SLC7A11 to prevent ferroptosis [127]. Together, these results highlight a therapy strategy combining LncRNA DUXAP8 silencing with sorafenib to overcome drug resistance to sorafenib in advanced HCC [127]. Previous study has shown that lncRNA CASC11 promotes HCC growth and metastasis through binding to stabilize ubiquitin-conjugating enzyme E2T (UBE2T) mRNA [143]. Further study revealed that lncRNA CASC11 promotes HCC tumour malignancy through inhibiting ferroptosis [128]. Silencing or overexpression lncRNA CASC11 enhances or inhibits sorafenib-induced ferroptosis in HCC cells, respectively [128]. Silencing lncRNA CASC11-mediated enhanced anticancer effect of sorafenib was reversed by Ferrostatin-1 (Ferr-1), a ferroptosis inhibitorin HCC cells. Mechanistical study has revealed that lncRNACASC11 binds to stabilize SLC7A11 mRNA. LncRNA CASC11 inhibits sorafenib-induced ferroptosis via stabilizing SLC7A11 [128]. SLC7A11-AS1 promotes HCC cell growth and resistance to erastin-induced ferroptosis through stabilizing SLC7A11 mRNA [129]. LncRNA HEPFAL accelerates ferroptosis by promoting the ubiquitination of SLC7A11 to reduce its protein stability [130]. LncRNA NRAV promotes HCC tumorigenesis and inhibits ferroptosis through upregulating SLC7A11 via sponging miR-375-3P and attenuates its the inhibitory effect on SLC7A11 [131].Table 2 The regulatory role of LncRNAs in modulation of ferroptosis in HCC

miRNA	Expression/function	Targets	Effects on tumour	Refs.	
LncRNA DUXAP8	↑/Oncogene	SLC7A11	Silencing LncRNA DUXAP8 boosts sorafenib-induced ferroptosis via de-palmitoylation of SLC7A11	[127]	
LncRNA CASC11	↑/Oncogene	SLC7A11	CASC11 inhibits sorafenib-induced ferroptosis via stabilizing SLC7A11	[128]	
LncRNA SLC7A11-AS1	↑/Oncogene	SLC7A11	SLC7A11-AS1 promots HCC cell growth and resistance to erastin-induced ferroptosis through stabilizing SLC7A11 mRNA	[129]	
LncRNA HEPFAL	↓/Tumor suppressor	SLC7A11	LncRNA HEPFAL accelerates ferroptosis by promoting the ubiquitination and degradation of SLC7A11 protein	[130]	
LncRNA NRAV	↑/Oncogene	miR-375-3P/SLC7A11	LncRNA NRAV promotes HCC tumorigenesis and inhibits ferroptosis through upregulating SLC7A11 via sponging miR-375-3P and attenuates its the inhibitory effect on SLC7A11	[131]	
LncPVT1	↑/Oncogene	GPX4	Overexpression of lncPVT1 and GPX4 impeded ketamine-induced ferroptosis	[132]	
LINC01134	↑/Oncogene	GPX4	LINC01134 decreased oxaliplatin sensitivity by inhibiting ferroptosis through upregulating GPX4	[133]	
LncRNA HCG18	↑/Oncogene	GPX4	Silencing HCG18 inhibits sorafenib resistance through promoting ferroptosis via inhibiting GPX4 by binding to miR-450b-5p	[134]	
LncRNA PVT1	-/Oncogene	miR-195-5p/PLAG1/GPX4	LncRNA acts as a sponge for miR-195-5p to upregulate expression of PLAG1, which enhances the expression of GPX4, resulting in the inhibition of the ferroptosis signaling pathway	[135]	
LncFAL	↑/Oncogene	FSP1	HDLBP-mediated lncFAL stabilization promotes ferroptosis resistance by diminishing Trim69-dependent FSP1 degradation	[136]	
LncRNA URB1-AS1	↑/Oncogene	Ferritin	HIF-1α-mediated increased URB1-AS1 attenuates sorafenib-triggered ferroptosis by inducing ferritin phase separation and decreasing the cellular free iron content	[137]	
LncRNA SNHG1	↑/Oncogene	miR-199a	SNHG1 inhibits ferroptosis through upregulating FANCD2 and G6PD by sponging miR-199a	[138]	
LncRNA GABPB1-AS1	↑/Tumor suppressor	PRDX5	LncRNA GABPB1-AS1 forms RNA duplexes with GABPB1 mRNA to inhibit GABPB1 translation, downregulate expression of PRDX5, which ultimately leads to ferroptosis	[139]	
LncRNA NEAT1	↓/Tumor suppressor	MIOX	NEAT1 promotes erastin and RSL3-induced ferroptosis by upregulating MIOX in HCC cells	[140]	
LncRNA HULC	↑/Oncogene	miR-3200-5p/ATF4	Decreased lncRNA HULC triggers ferroptosis via inhibiting miR-3200-5p/ATF4 Axis	[141]	
LncRNA EPS15-AS1	↓/Tumor suppressor	EPS15/AKR1B1	EPS15-AS1 inhibits HCC cell activity and induces ferroptosis by decreasing EPS15 expression and thus downregulating AKR1B1 expression	[142]	
HIF-1α hypoxia inducible factor-1α, IREB2 iron-responsive element-binding protein 2, HCC hepatocellular carcinoma, TXNRD1 thioredoxin reductase 1, cCRCC clear cell renal cell carcinoma, SAT1 spermine N1‐acetyltransferase 1, MIOX Myo-inositol oxygenase, FTH1 ferritin heavy chain 1, TfR1 transferrin receptor 1, GPX4 glutathione peroxidase 4, ATF4 activating transcription factor 4

Fig. 4 lncRNA regulation of ferroptosis in HCC. LncRNAs may impact antiferroptotic defense systems, proferroptotic proteins, and undiscovered targets to modify cellular peroxyphospholipid homeostasis.

Targeting GPX4

Overexpression of lncPVT1 and GPX4 impeded ketamine-induced ferroptosis [132]. LINC01134 decreased oxaliplatin sensitivity by inhibiting ferroptosis through upregulating GPX4 [133]. Upregulated lncRNA HCG18 in HCC associates with sorafenib resistance. Silencing lncRNA HCG18 inhibits resistance to sorafenib through enhancing ferroptosis, which was reversed by GPX4 overexpression [134]. LncRNA HCG18 sponges miR-450b-5p to downregulate GPX4. Collectively, these results suggest silencing lncRNA HCG18 overcomes sorafenib resistance through inducing ferroptosis by sponging miR-450b-5p to inhibit GPX4 in HCC [134]. LncRNA acts as a sponge for miR-195-5p to upregulate expression of PLAG1, which enhances the expression of GPX4, resulting in the inhibition of the ferroptosis signaling pathway [135].

Targeting other factors

HDLBP-mediated lncFAL stabilization facilitates ferroptosis resistance by diminishing Trim69-dependent FSP1 degradation [136]. Hypoxia inducible factor-1α (HIF-1α)-induced upregulation of LncRNA URB1-AS1 was observed in samples of patients with sorafenib-resistance, associates with poor survival in HCC [137]. LncRNA URB1-AS1 inhibits sorafenib-mediated ferroptosis through decreasing the cellular content of free iron by inducing ferritin phase separation. LncRNA URB1-AS1 silencing increases the sensitivity of HCC cells to sorafenib in vivo [137]. Together, these results indicate that lncRNA URB1-AS1 promotes sorafenib resistance through inhibiting ferroptosis, highlighting a therapy strategy combining lncRNA URB1-AS1 silencing with sorafenib to overcome drug resistance to sorafenib in HCC [137]. LncRNA SNHG1 inhibits ferroptosis through upregulating FANCD2 and G6PD by sponging miR-199a [138]. LncRNA GABPB1-AS1 forms RNA duplexes with GABPB1 mRNA to then inhibit GABPB1 translation, resulting in reduced expression of PRDX5, which ultimately leads to ferroptosis [139]. LncRNA NEAT1 promotes erastinand RSL3-induced ferroptosis by upregulating MIOX in HCC cells [140]. Decreased lncRNA HULC induces ferroptosis via inhibiting the miR-3200-5p/ATF4 Axis [141]. LncRNA EPS15-AS1 inhibits HCC cell activity and induces ferroptosis by decreasing EPS15 expression and thus downregulated AKR1B1 expression [142].

The regulatory role of circRNAs in modulating ferroptosis in HCC

Targeting GPX4

CircIL4R facilitates the tumorigenesis and suppresses ferroptosis by enhancing GPX4 expression by sponging and inhibiting miR541‐3p [144] (Table 3 and Fig. 5). circIDE inhibits HCC cell growth and facilitating ferroptosis through attenuating the expression of GPX4 by elevating RBMS1 expression via sponging miR-19b-3p [145]. circFAM134B target FAM134B–mediated ER-phagy to promote lenvatinib-induced ferroptosis in HCC cells. circFAM134B competitively interacts with PABPC4, thereby influencing FAM134B mRNA nonsense decay [146]. circ0060467 facilitates the tumorigenesis and inhibits ferroptosis through enhancing AIFM2 and GPX4 expression by sponging and inhibiting miR-6085[147]. Silencing circ_0016142 suppresses HCC cell proliferation by inducing ferroptosis via the miR-188-3p/GPX4 axis [148].Table 3 The regulatory role of circRNAs in modulation of ferroptosis in HCC

miRNA	Expression/function	Targets	Effects on tumour	Refs.	
CircIL4R	↑/Oncogene	GPX4	CircIL4R facilitates the tumorigenesis through inhibiting ferroptosis by enhancing GPX4 expression by sponging and inhibiting miR541‐3p	[144]	
circ_0000251	?/Tumor suppressor	miR-19b-3p/RBMS1/GPX4	circIDE inhibits HCC cell growth and facilitating ferroptosis through attenuating the expression of GPX4 by elevating RBMS1 expression via sponging miR-19b-3p	[145]	
circFAM134B	?/Tumor suppressor	SLC7A11/GPX4	circFAM134B target FAM134B–mediated ER-phagy to promote lenvatinib-induced ferroptosis in HCC cells. circFAM134B competitively interacts with PABPC4, thereby influencing FAM134B mRNA nonsense decay	[146]	
circ0060467	↑/Oncogene	GPX4 and AIFM2	circ0060467 facilitates the tumorigenesis and inhibits ferroptosis through enhancing AIFM2 and GPX4 expression by sponging and inhibiting miR-6085	[147]	
circ_0016142	↑/Oncogene	miR-188-3p/GPX4	Silencing circ_0016142 suppresses HCC cell proliferation by inducing ferroptosis via the miR-188-3p/GPX4 axis	[148]	
circ0097009	↑/Oncogene	SLC7A11	circ0097009 inhibits ferroptosis through upregulating SLC7A11 by sponging and inhibiting miR-1261	[149]	
circUPF2	↑/Oncogene	IGF2BP2-SLC7A11	circUPF2 enriched in exosomes promotes sorafenib resistance through suppressing ferroptosis via creation of the circUPF2-IGF2BP2-SLC7A11 ternary complex, thereby stabilizing SLC7A11 mRNA	[150]	
CircPIAS1	↑/Oncogene	NUPR1/FTH1	Overexpression of circPIAS1 inhibits ferroptosis by sponging and inhibiting miR-455-3p, leading to upregulation of NUPR1, which promotes FTH1 transcription and iron storage in HCC cells, conferring ferroptosis resistance. NUPR1 inhibitor ZZW-115 reverses the tumor-promoting effects of circPIAS1 and increases sensitivity of HCC cells to lenvatinib	[151]	
cIARS	↑/Oncogene	BCL-2/BECN1	Silencing cIARS suppresses sensitivity to sorafenib or Erastin through inhibiting ferroptosis, which may result from the inhibition of autophagy and ferritinophagy	[152]	
FTH1 ferritin heavy chain 1, TfR1 transferrin receptor 1, PABPC4 poly (A) binding protein cytoplasmic 4, NUPR1 nuclear protein 1

Fig. 5 circRNA regulation of ferroptosis in HCC. circRNAs may impact antiferroptotic defense systems, proferroptotic proteins, and undiscovered targets to modify cellular peroxyphospholipid homeostasis.

Targeting SLC7A11

Circ0097009 inhibits ferroptosis through upregulating SLC7A11 by sponging and inhibiting miR-1261 [149]. circUPF2 promotes resistance to sorafenib through inhibiting ferroptosis by upregulating SLC7A11 expression in HCC cells. Mechanistically, exosomal circUPF2 stabilizes SLC7A11 mRNA through enhancing the forming a ternary complex consisting of circUPF2-IGF2BP2-SLC7A11, thereby exosomal circUPF2 promotes SLC7A11 expression, leading to resistance to sorafenib in HCC [150].

Targeting other factors

Overexpression of circPIAS1 inhibits ferroptosis by sponging and inhibiting miR-455-3p, leading to upregulation of NUPR1, which enhances FTH1 transcription and iron storage in HCC cells, thereby conferring ferroptosis resistance. NUPR1 inhibitor ZZW-115 reverses the tumor-promoting effects of circPIAS1 and increases sensitivity of HCC cells to lenvatinib [151]. Upregulated hsa_circ_0008367 (cIARS) was observed in HCC cells after sorafenib treatment. Silencing cIARS inhibits sorafenib or erastin-induced ferroptosis, evidenced by reduced MDA and Fe2+, while increased intracellular GSH, indicating cIARS functions as a inducer of ferroptosis in HCC cells [152]. cIARS interacts with RNA binding protein alkylation repair homolog protein 5 (ALKBH5), the m6A demethylase works as a negative regulator of autophagic flux in HCC. Silencing cIARS blocks ALKBH5 silencing-mediated dissociation of BCL-2/BECN1 complex. Silencing ALKBH5 inhibits cIARS knockdown mediated autophagic flux and ferritinophagy [152]. In summary, cIARS promotes resiatance to sorafenib through inhibiting ferroptosis via suppressing the ALKBH5-mediated autophagy inhibition [152].

Conclusions and perspectives

In the present review, we aim to summarize the regulatory mechanisms and roles of ncRNA-mediated epigenetic modification on ferroptosis in HCC. We have analyzed the functional role of miRNAs, lncRNAs, and circRNAs in the regulation of ferroptosis in in cancer drug resistance. NcRNAs play vital roles in regulating ferroptosis through many aspects, including lipid metabolism, iron metabolism, and ferroptosis defense systems. circRNAs and lncRNA commonly works as molecular sponges for miRNAs, exerting regulatory functions in HCC.

However, the research on ncRNAs-mediated epigenetic modification regulating ferroptosis in HCC still in its infancy. There are still much limitations and challenges needed to bridge the gap in the current research. First, research on the role of ncRNAs-mediated epigenetic modification of ferroptosis in HCC is still ongoing, and other specific ncRNAs regulating ferroptosis warrant further study. Second, ncRNAs-mediated epigenetic modification of ferroptosis is identified in HCC, when small molecule compounds can feasibly targeted these ncRNAs-mediated dysregulated epigenetic mechanisms still have a long way to go. Third, ncRNAs participate in regulating crosstalk between ferroptosis with other regulated cell death in cancer [153]. However, role of ncRNA in interplay between ferroptosis and other regulated cell death, such as cuproptosis in HCC is largely unknown. Fourth, the included studies principally emphasized ncRNAs regulate the core mechanism of ferroptosis in HCC, i.e., they primarily focused on classical pathway, such as the SLC7A11-GPX4 system or ACSL4-dependant lipid peroxitation. However, the effects of other ferroptosis defence systems, including the DHODH-CoQH2 system, FSP 1-ubiquinol system, and GCH1-BH4 system, MBOAT1/2-MUFA system and SC5D-7-DHC axis is largely unknown. Fifth, mounting ncRNAs directly regulates ferroptosis through modulating ferroptosis related proteins or enzymes involved in iron metabolism, antioxidant defense, and lipid metabolism, or indirectly target other modulators of ferroptosis, such as transcription factors ATF4 in HCC. However, whether ncRNAs regulate other transcription factors, such as Nrf2 in HCC is still poorly understood.

Over the past decade, the clinical application of RNA-based therapeutics has made great effort, employing mostly small interfering RNAs and antisense oligonucleotides (ASO), with several gaining FDA approval as noted in a previous review [154]. Many miRNA mimics and anti-miRNAs therapeutics are in phase II or III clinical development, but no lncRNA-based therapeutics or circRNA-targeted treatments have entered the clinic as noted in a previous review [154–156]. Emerging evidence has shown that ncRNAs can be targeted by small-molecule compounds, making them become potential druggable targets for cancers [157]. Small molecules targeting miRNAs [158], lncRNA [159] or circRNA [160] regulating ferroptosis maybe offers a new opportunities in cancer therapy. However, there is no small molecules targeting ncRNA regulating ferroptosis have entered the clinic in cancer.

Taken together, emerging evidence have revealed that ncRNAs modulatetumour malignancy through regulating ferroptosis via proteins or genes involved in the core mechanism of ferroptosis or its regulators in HCC. This review summarize the recent progress in understanding of the ncRNA-mediated regulated mechanisms on ferroptosis in HCC. The review will promote our understanding of the ncRNA-mediated epigenetic regulatory mechanisms modulating ferroptosis in malignancy of HCC, highlighting a novel strategies for treatment of HCC through targeting ncRNA-ferroptosis axis.

Acknowledgements

No applicable.

Author contributions

LS, HC, and HW designed and conceived the Review. LS and HC contributed substantially to discussion of the content. LS and HW wrote the manuscript. HW generated the figures. HW edited the manuscript. All authors contributed to reviewing and/or editing of manuscript. All authors approved the final manuscript.

Funding

Not applicable.

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All of the authors are aware of and agree to the content of the paper and their being listed as a co-author of the paper.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Adhikari S Bhattacharya A Adhikary S Singh V Gadad SS Roy S The paradigm of drug resistance in cancer: an epigenetic perspective Biosci Rep. 2022 424 4 BSR20211812 10.1042/BSR20211812
Adhikari S, Bhattacharya A, Adhikary S, Singh V, Gadad SS, Roy S, et al. The paradigm of drug resistance in cancer: an epigenetic perspective. Biosci Rep. 2022;424(4):BSR20211812.10.1042/BSR20211812
2. Bukowski K Kciuk M Kontek R Mechanisms of multidrug resistance in cancer chemotherapy Int J Mol Sci. 2020 21 9 3233 10.3390/ijms21093233 32370233
Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21(9):3233.32370233 10.3390/ijms21093233
3. Villanueva A Hepatocellular carcinoma N Engl J Med 2019 380 1450 1462 10.1056/NEJMra1713263 30970190
Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380:1450–62.30970190 10.1056/NEJMra1713263
4. Llovet JM Kelley RK Villanueva A Singal AG Pikarsky E Roayaie S Hepatocellular carcinoma Nat Rev Dis Primers 2021 7 6 10.1038/s41572-020-00240-3 33479224
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.33479224 10.1038/s41572-020-00240-3
5. Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A Bray F Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2021 71 209 249 10.3322/caac.21660 33538338
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.33538338 10.3322/caac.21660
6. Vogel A Meyer T Sapisochin G Salem R Saborowski A Hepatocellular carcinoma Lancet 2022 400 1345 1362 10.1016/S0140-6736(22)01200-4 36084663
Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345–62.36084663 10.1016/S0140-6736(22)01200-4
7. Llovet JM Willoughby CE Singal AG Greten TF Heikenwälder M El-Serag HB Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment Nat Rev Gastroenterol Hepatol 2023 20 487 503 10.1038/s41575-023-00754-7 36932227
Llovet JM, Willoughby CE, Singal AG, Greten TF, Heikenwälder M, El-Serag HB, et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol. 2023;20:487–503.36932227 10.1038/s41575-023-00754-7
8. Wang Y Fleishman JS Li T Li Y Ren Z Chen J Pharmacological therapy of metabolic dysfunction-associated steatotic liver disease-driven hepatocellular carcinoma Front Pharmacol 2023 14 1336216 10.3389/fphar.2023.1336216 38313077
Wang Y, Fleishman JS, Li T, Li Y, Ren Z, Chen J, et al. Pharmacological therapy of metabolic dysfunction-associated steatotic liver disease-driven hepatocellular carcinoma. Front Pharmacol. 2023;14:1336216.38313077 10.3389/fphar.2023.1336216
9. Anstee QM Reeves HL Kotsiliti E Govaere O Heikenwalder M From NASH to HCC: current concepts and future challenges Nat Rev Gastroenterol Hepatol 2019 16 411 428 10.1038/s41575-019-0145-7 31028350
Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol. 2019;16:411–28.31028350 10.1038/s41575-019-0145-7
10. Llovet JM Castet F Heikenwalder M Maini MK Mazzaferro V Pinato DJ Immunotherapies for hepatocellular carcinoma Nat Rev Clin Oncol 2022 19 151 172 10.1038/s41571-021-00573-2 34764464
Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19:151–72.34764464 10.1038/s41571-021-00573-2
11. Yang X Yang C Zhang S Geng H Zhu AX Bernards R Precision treatment in advanced hepatocellular carcinoma Cancer Cell 2024 42 180 197 10.1016/j.ccell.2024.01.007 38350421
Yang X, Yang C, Zhang S, Geng H, Zhu AX, Bernards R, et al. Precision treatment in advanced hepatocellular carcinoma. Cancer Cell. 2024;42:180–97.38350421 10.1016/j.ccell.2024.01.007
12. Su X Li Y Ren Y Cao M Yang G Luo J A new strategy for overcoming drug resistance in liver cancer: epigenetic regulation Biomed Pharmacother 2024 176 116902 10.1016/j.biopha.2024.116902 38870626
Su X, Li Y, Ren Y, Cao M, Yang G, Luo J, et al. A new strategy for overcoming drug resistance in liver cancer: epigenetic regulation. Biomed Pharmacother. 2024;176:116902.38870626 10.1016/j.biopha.2024.116902
13. Lei YR He XL Li J Mo CF Drug resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects Front Biosci (Landmark Ed) 2024 29 52 10.31083/j.fbl2902052 38420802
Lei YR, He XL, Li J, Mo CF. Drug resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Front Biosci (Landmark Ed). 2024;29:52.38420802 10.31083/j.fbl2902052
14. Haider T Pandey V Banjare N Gupta PN Soni V Drug resistance in cancer: mechanisms and tackling strategies Pharmacol Rep 2020 72 5 1125 1151 10.1007/s43440-020-00138-7 32700248
Haider T, Pandey V, Banjare N, Gupta PN, Soni V. Drug resistance in cancer: mechanisms and tackling strategies. Pharmacol Rep. 2020;72(5):1125–51.32700248 10.1007/s43440-020-00138-7
15. Ramos P Bentires-Alj M Mechanism-based cancer therapy: resistance to therapy, therapy for resistance Oncogene 2015 34 28 3617 3626 10.1038/onc.2014.314 25263438
Ramos P, Bentires-Alj M. Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. Oncogene. 2015;34(28):3617–26.25263438 10.1038/onc.2014.314
16. Nussinov R Tsai CJ Jang H Anticancer drug resistance: an update and perspective Drug Resist Updat 2021 59 100796 10.1016/j.drup.2021.100796 34953682
Nussinov R, Tsai CJ, Jang H. Anticancer drug resistance: an update and perspective. Drug Resist Updat. 2021;59:100796.34953682 10.1016/j.drup.2021.100796
17. Lei G Zhuang L Gan B Targeting ferroptosis as a vulnerability in cancer Nat Rev Cancer 2022 22 7 381 396 10.1038/s41568-022-00459-0 35338310
Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381–96.35338310 10.1038/s41568-022-00459-0
18. Guo J Xu B Han Q Zhou H Xia Y Gong C Dai X Li Z Wu G Ferroptosis: a novel anti-tumor action for cisplatin Cancer Res Treat 2018 50 2 445 460 10.4143/crt.2016.572 28494534
Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, Dai X, Li Z, Wu G. Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat. 2018;50(2):445–60.28494534 10.4143/crt.2016.572
19. Lei G Zhang Y Koppula P Liu X Zhang J Lin SH Ajani JA Xiao Q Liao Z Wang H The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression Cell Res 2020 30 2 146 162 10.1038/s41422-019-0263-3 31949285
Lei G, Zhang Y, Koppula P, Liu X, Zhang J, Lin SH, Ajani JA, Xiao Q, Liao Z, Wang H, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 2020;30(2):146–62.31949285 10.1038/s41422-019-0263-3
20. Sun X Ou Z Chen R Niu X Chen D Kang R Tang D Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells Hepatology 2016 63 1 173 184 10.1002/hep.28251 26403645
Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, Tang D. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63(1):173–84.26403645 10.1002/hep.28251
21. Wang W Green M Choi JE Gijón M Kennedy PD Johnson JK Liao P Lang X Kryczek I Sell A CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy Nature 2019 569 7755 270 274 10.1038/s41586-019-1170-y 31043744
Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, Liao P, Lang X, Kryczek I, Sell A, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569(7755):270–4.31043744 10.1038/s41586-019-1170-y
22. Dai E Chen X Linkermann A Jiang X Kang R Kagan VE Bayir H Yang WS Garcia-Saez AJ Ioannou MS A guideline on the molecular ecosystem regulating ferroptosis Nat Cell Biol. 2024 10.1038/s41556-024-01360-8 38997456
Dai E, Chen X, Linkermann A, Jiang X, Kang R, Kagan VE, Bayir H, Yang WS, Garcia-Saez AJ, Ioannou MS, et al. A guideline on the molecular ecosystem regulating ferroptosis. Nat Cell Biol. 2024. 10.1038/s41556-024-01360-8.38997456 10.1038/s41556-024-01360-8
23. Dixon SJ Lemberg KM Lamprecht MR Skouta R Zaitsev EM Gleason CE Patel DN Bauer AJ Cantley AM Yang WS Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 5 1060 1072 10.1016/j.cell.2012.03.042 22632970
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.22632970 10.1016/j.cell.2012.03.042
24. Lei G Mao C Yan Y Zhuang L Gan B Ferroptosis, radiotherapy, and combination therapeutic strategies Protein Cell 2021 12 836 857 10.1007/s13238-021-00841-y 33891303
Lei G, Mao C, Yan Y, Zhuang L, Gan B. Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein Cell. 2021;12:836–57.33891303 10.1007/s13238-021-00841-y
25. Stockwell BR Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications Cell 2022 185 14 2401 2421 10.1016/j.cell.2022.06.003 35803244
Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185(14):2401–21.35803244 10.1016/j.cell.2022.06.003
26. Wang H Cheng Y Mao C Liu S Xiao D Huang J Emerging mechanisms and targeted therapy of ferroptosis in cancer Mol Ther 2021 29 2185 2208 10.1016/j.ymthe.2021.03.022 33794363
Wang H, Cheng Y, Mao C, Liu S, Xiao D, Huang J, et al. Emerging mechanisms and targeted therapy of ferroptosis in cancer. Mol Ther. 2021;29:2185–208.33794363 10.1016/j.ymthe.2021.03.022
27. Elgendy SM Alyammahi SK Alhamad DW Abdin SM Omar HA Ferroptosis: an emerging approach for targeting cancer stem cells and drug resistance Crit Rev Oncol Hematol 2020 155 103095 10.1016/j.critrevonc.2020.103095 32927333
Elgendy SM, Alyammahi SK, Alhamad DW, Abdin SM, Omar HA. Ferroptosis: an emerging approach for targeting cancer stem cells and drug resistance. Crit Rev Oncol Hematol. 2020;155:103095.32927333 10.1016/j.critrevonc.2020.103095
28. Friedmann Angeli JP Krysko DV Conrad M Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion Nat Rev Cancer 2019 19 7 405 414 10.1038/s41568-019-0149-1 31101865
Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019;19(7):405–14.31101865 10.1038/s41568-019-0149-1
29. Liu X Zhang Y Wu X Xu F Ma H Wu M Xia Y Targeting ferroptosis pathway to combat therapy resistance and metastasis of cancer Front Pharmacol 2022 13 909821 10.3389/fphar.2022.909821 35847022
Liu X, Zhang Y, Wu X, Xu F, Ma H, Wu M, Xia Y. Targeting ferroptosis pathway to combat therapy resistance and metastasis of cancer. Front Pharmacol. 2022;13:909821.35847022 10.3389/fphar.2022.909821
30. Ozkan E Bakar-Ates F Ferroptosis: a trusted ally in combating drug resistance in cancer Curr Med Chem 2022 29 1 41 55 10.2174/0929867328666210810115812 34375173
Ozkan E, Bakar-Ates F. Ferroptosis: a trusted ally in combating drug resistance in cancer. Curr Med Chem. 2022;29(1):41–55.34375173 10.2174/0929867328666210810115812
31. Wang Y Wu X Ren Z Li Y Zou W Chen J Wang H Overcoming cancer chemotherapy resistance by the induction of ferroptosis Drug Resist Updat 2023 66 100916 10.1016/j.drup.2022.100916 36610291
Wang Y, Wu X, Ren Z, Li Y, Zou W, Chen J, Wang H. Overcoming cancer chemotherapy resistance by the induction of ferroptosis. Drug Resist Updat. 2023;66:100916.36610291 10.1016/j.drup.2022.100916
32. Zhang C Liu X Jin S Chen Y Guo R Ferroptosis in cancer therapy: a novel approach to reversing drug resistance Mol Cancer 2022 21 1 47 10.1186/s12943-022-01530-y 35151318
Zhang C, Liu X, Jin S, Chen Y, Guo R. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer. 2022;21(1):47.35151318 10.1186/s12943-022-01530-y
33. Lin X Wu Z Hu H Luo ML Song E Non-coding RNAs rewire cancer metabolism networks Semin Cancer Biol 2021 75 116 126 10.1016/j.semcancer.2020.12.019 33421618
Lin X, Wu Z, Hu H, Luo ML, Song E. Non-coding RNAs rewire cancer metabolism networks. Semin Cancer Biol. 2021;75:116–26.33421618 10.1016/j.semcancer.2020.12.019
34. Balihodzic A Prinz F Dengler MA Calin GA Jost PJ Pichler M Non-coding RNAs and ferroptosis: potential implications for cancer therapy Cell Death Differ 2022 29 6 1094 1106 10.1038/s41418-022-00998-x 35422492
Balihodzic A, Prinz F, Dengler MA, Calin GA, Jost PJ, Pichler M. Non-coding RNAs and ferroptosis: potential implications for cancer therapy. Cell Death Differ. 2022;29(6):1094–106.35422492 10.1038/s41418-022-00998-x
35. Ensoy M Bumin ZS Jama HA Cansaran-Duman D The regulation role of ferroptosis mechanism of anti-cancer drugs and noncoding RNAs Curr Med Chem 2023 30 14 1638 1656 10.2174/0929867329666220629154418 35770401
Ensoy M, Bumin ZS, Jama HA, Cansaran-Duman D. The regulation role of ferroptosis mechanism of anti-cancer drugs and noncoding RNAs. Curr Med Chem. 2023;30(14):1638–56.35770401 10.2174/0929867329666220629154418
36. Luo Y Huang Q He B Liu Y Huang S Xiao J Regulation of ferroptosis by non-coding RNAs in the development and treatment of cancer (Review) Oncol Rep 2021 45 1 29 48 10.3892/or.2020.7836 33155665
Luo Y, Huang Q, He B, Liu Y, Huang S, Xiao J. Regulation of ferroptosis by non-coding RNAs in the development and treatment of cancer (Review). Oncol Rep. 2021;45(1):29–48.33155665 10.3892/or.2020.7836
37. Valashedi MR Bamshad C Najafi-Ghalehlou N Nikoo A Tomita K Kuwahara Y Sato T Roushandeh AM Roudkenar MH Non-coding RNAs in ferroptotic cancer cell death pathway: meet the new masters Hum Cell 2022 35 4 972 994 10.1007/s13577-022-00699-0 35415781
Valashedi MR, Bamshad C, Najafi-Ghalehlou N, Nikoo A, Tomita K, Kuwahara Y, Sato T, Roushandeh AM, Roudkenar MH. Non-coding RNAs in ferroptotic cancer cell death pathway: meet the new masters. Hum Cell. 2022;35(4):972–94.35415781 10.1007/s13577-022-00699-0
38. Wang D Tang L Zhang Y Ge G Jiang X Mo Y Wu P Deng X Li L Zuo S Regulatory pathways and drugs associated with ferroptosis in tumors Cell Death Dis 2022 13 6 544 10.1038/s41419-022-04927-1 35688814
Wang D, Tang L, Zhang Y, Ge G, Jiang X, Mo Y, Wu P, Deng X, Li L, Zuo S, et al. Regulatory pathways and drugs associated with ferroptosis in tumors. Cell Death Dis. 2022;13(6):544.35688814 10.1038/s41419-022-04927-1
39. Xie B Guo Y Molecular mechanism of cell ferroptosis and research progress in regulation of ferroptosis by noncoding RNAs in tumor cells Cell Death Discov 2021 7 1 101 10.1038/s41420-021-00483-3 33980834
Xie B, Guo Y. Molecular mechanism of cell ferroptosis and research progress in regulation of ferroptosis by noncoding RNAs in tumor cells. Cell Death Discov. 2021;7(1):101.33980834 10.1038/s41420-021-00483-3
40. Zuo YB Zhang YF Zhang R Tian JW Lv XB Li R Li SP Cheng MD Shan J Zhao Z Ferroptosis in cancer progression: role of noncoding RNAs Int J Biol Sci 2022 18 5 1829 1843 10.7150/ijbs.66917 35342359
Zuo YB, Zhang YF, Zhang R, Tian JW, Lv XB, Li R, Li SP, Cheng MD, Shan J, Zhao Z, et al. Ferroptosis in cancer progression: role of noncoding RNAs. Int J Biol Sci. 2022;18(5):1829–43.35342359 10.7150/ijbs.66917
41. Gu Y Li Y Wang J Zhang L Zhang J Wang Y Targeting ferroptosis: paving new roads for drug design and discovery Eur J Med Chem 2023 247 115015 10.1016/j.ejmech.2022.115015 36543035
Gu Y, Li Y, Wang J, Zhang L, Zhang J, Wang Y. Targeting ferroptosis: paving new roads for drug design and discovery. Eur J Med Chem. 2023;247:115015.36543035 10.1016/j.ejmech.2022.115015
42. Huo L Liu C Yuan Y Liu X Cao Q Pharmacological inhibition of ferroptosis as a therapeutic target for sepsis-associated organ damage Eur J Med Chem 2023 257 115438 10.1016/j.ejmech.2023.115438 37269668
Huo L, Liu C, Yuan Y, Liu X, Cao Q. Pharmacological inhibition of ferroptosis as a therapeutic target for sepsis-associated organ damage. Eur J Med Chem. 2023;257:115438.37269668 10.1016/j.ejmech.2023.115438
43. Yin L Liu P Jin Y Ning Z Yang Y Gao H Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications Eur J Med Chem 2022 244 114861 10.1016/j.ejmech.2022.114861 36332549
Yin L, Liu P, Jin Y, Ning Z, Yang Y, Gao H. Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications. Eur J Med Chem. 2022;244:114861. 10.1016/j.ejmech.2022.114861.36332549 10.1016/j.ejmech.2022.114861
44. Wang Y Hu J Wu S Fleishman JS Li Y Xu Y Zou W Wang J Feng Y Chen J Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases Signal Transduct Target Ther 2023 8 1 449 10.1038/s41392-023-01720-0 38072908
Wang Y, Hu J, Wu S, Fleishman JS, Li Y, Xu Y, Zou W, Wang J, Feng Y, Chen J, et al. Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases. Signal Transduct Target Ther. 2023;8(1):449.38072908 10.1038/s41392-023-01720-0
45. Dixon SJ Olzmann JA The cell biology of ferroptosis Nat Rev Mol Cell Biol 2024 25 6 424 442 10.1038/s41580-024-00703-5 38366038
Dixon SJ, Olzmann JA. The cell biology of ferroptosis. Nat Rev Mol Cell Biol. 2024;25(6):424–42.38366038 10.1038/s41580-024-00703-5
46. Chen X Kang R Kroemer G Tang D Ferroptosis in infection, inflammation, and immunity J Exp Med 2021 218 e20210518 10.1084/jem.20210518 33978684
Chen X, Kang R, Kroemer G, Tang D. Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021;218:e20210518.33978684 10.1084/jem.20210518
47. Hadian K Stockwell BR SnapShot: ferroptosis Cell 2020 181 5 1188 1188.e1 10.1016/j.cell.2020.04.039 32470402
Hadian K, Stockwell BR. SnapShot: ferroptosis. Cell. 2020;181(5):1188-1188.e1.32470402 10.1016/j.cell.2020.04.039
48. Pope LE Dixon SJ Regulation of ferroptosis by lipid metabolism Trends Cell Biol 2023 33 12 1077 1087 10.1016/j.tcb.2023.05.003 37407304
Pope LE, Dixon SJ. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 2023;33(12):1077–87.37407304 10.1016/j.tcb.2023.05.003
49. Jiang X Stockwell BR Conrad M Ferroptosis: mechanisms, biology and role in disease Nat Rev Mol Cell Biol 2021 22 266 282 10.1038/s41580-020-00324-8 33495651
Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–82.33495651 10.1038/s41580-020-00324-8
50. Gan B Mitochondrial regulation of ferroptosis J Cell Biol 2021 220 e202105043 10.1083/jcb.202105043 34328510
Gan B. Mitochondrial regulation of ferroptosis. J Cell Biol. 2021;220:e202105043.34328510 10.1083/jcb.202105043
51. Gao M Yi J Zhu J Minikes AM Monian P Thompson CB Role of mitochondria in ferroptosis Mol Cell 2019 73 354 63.e3 10.1016/j.molcel.2018.10.042 30581146
Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell. 2019;73:354-63.e3.30581146 10.1016/j.molcel.2018.10.042
52. Stockwell BR Friedmann Angeli JP Bayir H Bush AI Conrad M Dixon SJ Fulda S Gascón S Hatzios SK Kagan VE Ferroptosis: a regulated cell death nexus linking metabolism Redox Biol Dis Cell 2017 171 2 273 285
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, et al. Ferroptosis: a regulated cell death nexus linking metabolism. Redox Biol Dis Cell. 2017;171(2):273–85.
53. Zhang DD Ironing out the details of ferroptosis Nat Cell Biol. 2024 10.1038/s41556-024-01361-7 39261719
Zhang DD. Ironing out the details of ferroptosis. Nat Cell Biol. 2024. 10.1038/s41556-024-01361-7.39261719 10.1038/s41556-024-01361-7
54. Liang D Minikes AM Jiang X Ferroptosis at the intersection of lipid metabolism and cellular signaling Mol Cell 2022 82 12 2215 2227 10.1016/j.molcel.2022.03.022 35390277
Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 2022;82(12):2215–27.35390277 10.1016/j.molcel.2022.03.022
55. Doll S Conrad M Iron and ferroptosis: A still ill-defined liaison IUBMB Life 2017 69 6 423 434 10.1002/iub.1616 28276141
Doll S, Conrad M. Iron and ferroptosis: A still ill-defined liaison. IUBMB Life. 2017;69(6):423–34.28276141 10.1002/iub.1616
56. Helberg J Pratt DA Autoxidation vs. antioxidants—the fight for forever Chem Soc Rev 2021 50 7343 7358 10.1039/D1CS00265A 34037013
Helberg J, Pratt DA. Autoxidation vs. antioxidants—the fight for forever. Chem Soc Rev. 2021;50:7343–58.34037013 10.1039/D1CS00265A
57. Conrad M Pratt DA The chemical basis of ferroptosis Nat Chem Biol 2019 15 1137 1147 10.1038/s41589-019-0408-1 31740834
Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol. 2019;15:1137–47.31740834 10.1038/s41589-019-0408-1
58. Doll S Proneth B Tyurina YY Panzilius E Kobayashi S Ingold I ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition Nat Chem Biol 2017 13 91 98 10.1038/nchembio.2239 27842070
Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–8.27842070 10.1038/nchembio.2239
59. Kagan VE Mao G Qu F Angeli JP Doll S Croix CS Dar HH Liu B Tyurin VA Ritov VB Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis Nat Chem Biol 2017 13 1 81 90 10.1038/nchembio.2238 27842066
Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, Dar HH, Liu B, Tyurin VA, Ritov VB, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81–90.27842066 10.1038/nchembio.2238
60. Yang WS Kim KJ Gaschler MM Patel M Shchepinov MS Stockwell BR Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis Proc Natl Acad Sci USA 2016 113 34 E4966 4975 10.1073/pnas.1603244113 27506793
Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 2016;113(34):E4966-4975.27506793 10.1073/pnas.1603244113
61. Yan B Ai Y Sun Q Ma Y Cao Y Wang J Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1 Mol Cell 2021 81 355 69.e10 10.1016/j.molcel.2020.11.024 33321093
Yan B, Ai Y, Sun Q, Ma Y, Cao Y, Wang J, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol Cell. 2021;81:355-69.e10.33321093 10.1016/j.molcel.2020.11.024
62. Zou Y Li H Graham ET Deik AA Eaton JK Wang W Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis Nat Chem Biol 2020 16 302 309 10.1038/s41589-020-0472-6 32080622
Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W, et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol. 2020;16:302–9.32080622 10.1038/s41589-020-0472-6
63. Poursaitidis I Wang X Crighton T Labuschagne C Mason D Cramer SL Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine Cell Rep 2017 18 2547 2556 10.1016/j.celrep.2017.02.054 28297659
Poursaitidis I, Wang X, Crighton T, Labuschagne C, Mason D, Cramer SL, et al. Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep. 2017;18:2547–56.28297659 10.1016/j.celrep.2017.02.054
64. Yang WH Ding CC Sun T Rupprecht G Lin CC Hsu D The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma Cell Rep 2019 28 2501 8.e4 10.1016/j.celrep.2019.07.107 31484063
Yang WH, Ding CC, Sun T, Rupprecht G, Lin CC, Hsu D, et al. The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma. Cell Rep. 2019;28:2501-8.e4.31484063 10.1016/j.celrep.2019.07.107
65. Chu B Kon N Chen D Li T Liu T Jiang L ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway Nat Cell Biol 2019 21 579 591 10.1038/s41556-019-0305-6 30962574
Chu B, Kon N, Chen D, Li T, Liu T, Jiang L, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol. 2019;21:579–91.30962574 10.1038/s41556-019-0305-6
66. Shah R Shchepinov MS Pratt DA Resolving the role of lipoxygenases in the initiation and execution of ferroptosis ACS Cent Sci 2018 4 3 387 396 10.1021/acscentsci.7b00589 29632885
Shah R, Shchepinov MS, Pratt DA. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent Sci. 2018;4(3):387–96.29632885 10.1021/acscentsci.7b00589
67. Anthonymuthu TS Tyurina YY Sun WY Mikulska-Ruminska K Shrivastava IH Tyurin VA Resolving the paradox of ferroptotic cell death: ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis Redox Biol 2021 38 101744 10.1016/j.redox.2020.101744 33126055
Anthonymuthu TS, Tyurina YY, Sun WY, Mikulska-Ruminska K, Shrivastava IH, Tyurin VA, et al. Resolving the paradox of ferroptotic cell death: ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis. Redox Biol. 2021;38:101744.33126055 10.1016/j.redox.2020.101744
68. Gaschler MM Hu F Feng H Linkermann A Min W Stockwell BR Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis ACS Chem Biol 2018 13 1013 1020 10.1021/acschembio.8b00199 29512999
Gaschler MM, Hu F, Feng H, Linkermann A, Min W, Stockwell BR. Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. ACS Chem Biol. 2018;13:1013–20.29512999 10.1021/acschembio.8b00199
69. Chen X Li J Kang R Klionsky DJ Tang D Ferroptosis: machinery and regulation Autophagy 2021 17 9 2054 2081 10.1080/15548627.2020.1810918 32804006
Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Autophagy. 2021;17(9):2054–81.32804006 10.1080/15548627.2020.1810918
70. Hassannia B Vandenabeele P Vanden BT Targeting ferroptosis to iron out cancer Cancer Cell 2019 35 6 830 849 10.1016/j.ccell.2019.04.002 31105042
Hassannia B, Vandenabeele P, Vanden BT. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35(6):830–49.31105042 10.1016/j.ccell.2019.04.002
71. Jacquemyn J Ralhan I Ioannou MS Driving factors of neuronal ferroptosis Trends Cell Biol. 2024 34 7 535 546 10.1016/j.tcb.2024.01.010 38395733
Jacquemyn J, Ralhan I, Ioannou MS. Driving factors of neuronal ferroptosis. Trends Cell Biol. 2024;34(7):535–46.38395733 10.1016/j.tcb.2024.01.010
72. Ayala A Muñoz MF Argüelles S Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal Oxid Med Cell Longev 2014 2014 360438 10.1155/2014/360438 24999379
Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.24999379 10.1155/2014/360438
73. Dos Santos AF Fazeli G Xavier da Silva TN Friedmann Angeli JP Ferroptosis: mechanisms and implications for cancer development and therapy response Trends Cell Biol 2023 33 1062 1073 10.1016/j.tcb.2023.04.005 37230924
Dos Santos AF, Fazeli G, Xavier da Silva TN, Friedmann Angeli JP. Ferroptosis: mechanisms and implications for cancer development and therapy response. Trends Cell Biol. 2023;33:1062–73.37230924 10.1016/j.tcb.2023.04.005
74. Ryter SW Kim HP Hoetzel A Mechanisms of cell death in oxidative stress Antioxid Redox Signal 2007 9 1 49 89 10.1089/ars.2007.9.49 17115887
Ryter SW, Kim HP, Hoetzel A, et al. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 2007;9(1):49–89.17115887 10.1089/ars.2007.9.49
75. Bao WD Pang P Zhou XT Hu F Xiong W Chen K Wang J Wang F Xie D Hu YZ Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease Cell Death Differ 2021 28 5 1548 1562 10.1038/s41418-020-00685-9 33398092
Bao WD, Pang P, Zhou XT, Hu F, Xiong W, Chen K, Wang J, Wang F, Xie D, Hu YZ, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ. 2021;28(5):1548–62.33398092 10.1038/s41418-020-00685-9
76. Chen PH Wu J Ding CC Lin CC Pan S Bossa N Xu Y Yang WH Mathey-Prevot B Chi JT Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism Cell Death Differ 2020 27 3 1008 1022 10.1038/s41418-019-0393-7 31320750
Chen PH, Wu J, Ding CC, Lin CC, Pan S, Bossa N, Xu Y, Yang WH, Mathey-Prevot B, Chi JT. Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism. Cell Death Differ. 2020;27(3):1008–22.31320750 10.1038/s41418-019-0393-7
77. Geng N Shi BJ Li SL Zhong ZY Li YC Xua WL Zhou H Cai JH Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells Eur Rev Med Pharmacol Sci 2018 22 12 3826 3836 29949159
Geng N, Shi BJ, Li SL, Zhong ZY, Li YC, Xua WL, Zhou H, Cai JH. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur Rev Med Pharmacol Sci. 2018;22(12):3826–36.29949159
78. Gao M Monian P Pan Q Zhang W Xiang J Jiang X Ferroptosis is an autophagic cell death process Cell Res 2016 26 9 1021 1032 10.1038/cr.2016.95 27514700
Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26(9):1021–32.27514700 10.1038/cr.2016.95
79. Hou W Xie Y Song X Sun X Lotze MT Zeh HJ 3rd Kang R Tang D Autophagy promotes ferroptosis by degradation of ferritin Autophagy 2016 12 8 1425 1428 10.1080/15548627.2016.1187366 27245739
Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, Kang R, Tang D. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12(8):1425–8.27245739 10.1080/15548627.2016.1187366
80. Gao M Monian P Quadri N Ramasamy R Jiang X Glutaminolysis and transferrin regulate ferroptosis Mol Cell 2015 59 2 298 308 10.1016/j.molcel.2015.06.011 26166707
Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59(2):298–308.26166707 10.1016/j.molcel.2015.06.011
81. Chen X Yu C Kang R Tang D Iron metabolism in ferroptosis Front Cell Dev Biol 2020 8 590226 10.3389/fcell.2020.590226 33117818
Chen X, Yu C, Kang R, Tang D. Iron metabolism in ferroptosis. Front Cell Dev Biol. 2020;8:590226.33117818 10.3389/fcell.2020.590226
82. David S Jhelum P Ryan F Jeong SY Kroner A Dysregulation of iron homeostasis in the central nervous system and the role of ferroptosis in neurodegenerative disorders Antioxid Redox Signal 2022 37 1–3 150 170 10.1089/ars.2021.0218 34569265
David S, Jhelum P, Ryan F, Jeong SY, Kroner A. Dysregulation of iron homeostasis in the central nervous system and the role of ferroptosis in neurodegenerative disorders. Antioxid Redox Signal. 2022;37(1–3):150–70.34569265 10.1089/ars.2021.0218
83. Dixon SJ Winter GE Musavi LS Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death ACS Chem Biol 2015 10 7 1604 1609 10.1021/acschembio.5b00245 25965523
Dixon SJ, Winter GE, Musavi LS, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10(7):1604–9.25965523 10.1021/acschembio.5b00245
84. Stockwell BR Jiang X The chemistry and biology of ferroptosis Cell Chem Biol 2020 27 4 365 375 10.1016/j.chembiol.2020.03.013 32294465
Stockwell BR, Jiang X. The chemistry and biology of ferroptosis. Cell Chem Biol. 2020;27(4):365–75.32294465 10.1016/j.chembiol.2020.03.013
85. Sun Y Xia X Basnet D Zheng JC Huang J Liu J Mechanisms of ferroptosis and emerging links to the pathology of neurodegenerative diseases Front Aging Neurosci 2022 14 904152 10.3389/fnagi.2022.904152 35837484
Sun Y, Xia X, Basnet D, Zheng JC, Huang J, Liu J. Mechanisms of ferroptosis and emerging links to the pathology of neurodegenerative diseases. Front Aging Neurosci. 2022;14:904152.35837484 10.3389/fnagi.2022.904152
86. Brigelius-Flohé R Flohé L Regulatory phenomena in the glutathione peroxidase superfamily Antioxid Redox Signal 2020 33 7 498 516 10.1089/ars.2019.7905 31822117
Brigelius-Flohé R, Flohé L. Regulatory phenomena in the glutathione peroxidase superfamily. Antioxid Redox Signal. 2020;33(7):498–516.31822117 10.1089/ars.2019.7905
87. Brigelius-Flohé R Maiorino M Glutathione peroxidases Biochim Biophys Acta 2013 1830 5 3289 3303 10.1016/j.bbagen.2012.11.020 23201771
Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta. 2013;1830(5):3289–303.23201771 10.1016/j.bbagen.2012.11.020
88. Seibt TM Proneth B Conrad M Role of GPX4 in ferroptosis and its pharmacological implication Free Radic Biol Med 2019 133 144 152 10.1016/j.freeradbiomed.2018.09.014 30219704
Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med. 2019;133:144–52.30219704 10.1016/j.freeradbiomed.2018.09.014
89. Ursini F Maiorino M Valente M Ferri L Gregolin C Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides Biochim Biophys Acta 1982 710 197 211 10.1016/0005-2760(82)90150-3 7066358
Ursini F, Maiorino M, Valente M, Ferri L, Gregolin C. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochim Biophys Acta. 1982;710:197–211.7066358 10.1016/0005-2760(82)90150-3
90. Yang WS SriRamaratnam R Welsch ME Shimada K Skouta R Viswanathan VS Regulation of ferroptotic cancer cell death by GPX4 Cell 2014 156 1–2 317 331 10.1016/j.cell.2013.12.010 24439385
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–31.24439385 10.1016/j.cell.2013.12.010
91. Ingold I Berndt C Schmitt S Doll S Poschmann G Buday K Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis Cell 2018 172 3 409 22.e21 10.1016/j.cell.2017.11.048 29290465
Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172(3):409-22.e21.29290465 10.1016/j.cell.2017.11.048
92. Forcina GC Dixon SJ GPX4 at the crossroads of lipid homeostasis and ferroptosis Proteomics 2019 19 18 e1800311 10.1002/pmic.201800311 30888116
Forcina GC, Dixon SJ. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 2019;19(18):e1800311.30888116 10.1002/pmic.201800311
93. Friedmann Angeli JP Schneider M Proneth B Tyurina YY Tyurin VA Hammond VJ Herbach N Aichler M Walch A Eggenhofer E Basavarajappa D Rådmark O Kobayashi S Seibt T Beck H Neff F Esposito I Wanke R Förster H Yefremova O Heinrichmeyer M Bornkamm GW Geissler EK Thomas SB Stockwell BR O'Donnell VB Kagan VE Schick JA Conrad M Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice Nat Cell Biol 2014 16 1180 1191 10.1038/ncb3064 25402683
Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O’Donnell VB, Kagan VE, Schick JA, Conrad M. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.25402683 10.1038/ncb3064
94. Koppula P Zhang Y Zhuang L Gan B Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer Cancer Commun (Lond) 2018 38 1 12 29764521
Koppula P, Zhang Y, Zhuang L, Gan B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun (Lond). 2018;38(1):12.29764521
95. Sato H Tamba M Ishii T Bannai S Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins J Biol Chem 1999 274 17 11455 11458 10.1074/jbc.274.17.11455 10206947
Sato H, Tamba M, Ishii T, Bannai S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem. 1999;274(17):11455–8.10206947 10.1074/jbc.274.17.11455
96. Bersuker K Hendricks JM Li Z Magtanong L Ford B Tang PH The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis Nature 2019 575 7784 688 692 10.1038/s41586-019-1705-2 31634900
Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–92.31634900 10.1038/s41586-019-1705-2
97. Doll S Freitas FP Shah R Aldrovandi M da Silva MC Ingold I FSP1 is a glutathione-independent ferroptosis suppressor Nature 2019 575 7784 693 698 10.1038/s41586-019-1707-0 31634899
Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–8.31634899 10.1038/s41586-019-1707-0
98. Nakamura T Hipp C Santos Dias Mourão A Borggräfe J Aldrovandi M Henkelmann B Wanninger J Mishima E Lytton E Emler D Proneth B Sattler M Conrad M Phase separation of FSP1 promotes ferroptosis Nature 2023 619 371 377 10.1038/s41586-023-06255-6 37380771
Nakamura T, Hipp C, Santos Dias Mourão A, Borggräfe J, Aldrovandi M, Henkelmann B, Wanninger J, Mishima E, Lytton E, Emler D, Proneth B, Sattler M, Conrad M. Phase separation of FSP1 promotes ferroptosis. Nature. 2023;619:371–7.37380771 10.1038/s41586-023-06255-6
99. Dai E Zhang W Cong D Kang R Wang J Tang D AIFM2 blocks ferroptosis independent of ubiquinol metabolism Biochem Biophys Res Commun 2020 523 4 966 971 10.1016/j.bbrc.2020.01.066 31964528
Dai E, Zhang W, Cong D, Kang R, Wang J, Tang D. AIFM2 blocks ferroptosis independent of ubiquinol metabolism. Biochem Biophys Res Commun. 2020;523(4):966–71.31964528 10.1016/j.bbrc.2020.01.066
100. Pedrera L Espiritu RA Ros U Ferroptotic pores induce Ca(2+) fluxes and ESCRT-III activation to modulate cell death kinetics Cell Death Differ 2021 28 5 1644 1657 10.1038/s41418-020-00691-x 33335287
Pedrera L, Espiritu RA, Ros U, et al. Ferroptotic pores induce Ca(2+) fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ. 2021;28(5):1644–57.33335287 10.1038/s41418-020-00691-x
101. Kraft V Bezjian CT Pfeiffer S Ringelstetter L Müller C Zandkarimi F Merl-Pham J Bao X Anastasov N Kössl J GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling ACS Cent Sci 2020 6 1 41 53 10.1021/acscentsci.9b01063 31989025
Kraft V, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, Merl-Pham J, Bao X, Anastasov N, Kössl J, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci. 2020;6(1):41–53.31989025 10.1021/acscentsci.9b01063
102. Soula M Weber RA Zilka O Alwaseem H La K Yen F Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers Nat Chem Biol 2020 16 12 1351 1360 10.1038/s41589-020-0613-y 32778843
Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F, et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol. 2020;16(12):1351–60.32778843 10.1038/s41589-020-0613-y
103. Mao C Liu X Zhang Y Lei G Yan Y Lee H Koppula P Wu S Zhuang L Fang B Poyurovsky MV Olszewski K Gan B DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer Nature 2021 593 586 590 10.1038/s41586-021-03539-7 33981038
Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, Koppula P, Wu S, Zhuang L, Fang B, Poyurovsky MV, Olszewski K, Gan B. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593:586–90.33981038 10.1038/s41586-021-03539-7
104. Liang D Feng Y Zandkarimi F Wang H Zhang Z Kim J Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones Cell 2023 186 13 2748 2764 10.1016/j.cell.2023.05.003 37267948
Liang D, Feng Y, Zandkarimi F, Wang H, Zhang Z, Kim J, et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell. 2023;186(13):2748–64.37267948 10.1016/j.cell.2023.05.003
105. Li Y Ran Q Duan Q Jin J Wang Y Yu L 7-Dehydrocholesterol dictates ferroptosis sensitivity Nature 2024 626 7998 411 418 10.1038/s41586-023-06983-9 38297130
Li Y, Ran Q, Duan Q, Jin J, Wang Y, Yu L, et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature. 2024;626(7998):411–8.38297130 10.1038/s41586-023-06983-9
106. Freitas FP Alborzinia H Dos Santos AF Nepachalovich P Pedrera L Zilka O 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis Nature 2024 626 7998 401 410 10.1038/s41586-023-06878-9 38297129
Freitas FP, Alborzinia H, Dos Santos AF, Nepachalovich P, Pedrera L, Zilka O, et al. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature. 2024;626(7998):401–10.38297129 10.1038/s41586-023-06878-9
107. Cavalli G Heard E Advances in epigenetics link genetics to the environment and disease Nature 2019 571 7766 489 499 10.1038/s41586-019-1411-0 31341302
Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019;571(7766):489–99.31341302 10.1038/s41586-019-1411-0
108. Cao J Yan Q Cancer epigenetics, tumor immunity, and immunotherapy Trends Cancer 2020 6 7 580 592 10.1016/j.trecan.2020.02.003 32610068
Cao J, Yan Q. Cancer epigenetics, tumor immunity, and immunotherapy. Trends Cancer. 2020;6(7):580–92.32610068 10.1016/j.trecan.2020.02.003
109. Hogg SJ Beavis PA Dawson MA Johnstone RW Targeting the epigenetic regulation of antitumour immunity Nat Rev Drug Discov 2020 19 776 800 10.1038/s41573-020-0077-5 32929243
Hogg SJ, Beavis PA, Dawson MA, Johnstone RW. Targeting the epigenetic regulation of antitumour immunity. Nat Rev Drug Discov. 2020;19:776–800.32929243 10.1038/s41573-020-0077-5
110. Wang N Ma T Yu B Targeting epigenetic regulators to overcome drug resistance in cancers Signal Transduct Target Ther 2023 8 1 69 10.1038/s41392-023-01341-7 36797239
Wang N, Ma T, Yu B. Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduct Target Ther. 2023;8(1):69.36797239 10.1038/s41392-023-01341-7
111. Garcia-Martinez L Zhang Y Nakata Y Chan HL Morey L Epigenetic mechanisms in breast cancer therapy and resistance Nat Commun 2021 12 1786 10.1038/s41467-021-22024-3 33741974
Garcia-Martinez L, Zhang Y, Nakata Y, Chan HL, Morey L. Epigenetic mechanisms in breast cancer therapy and resistance. Nat Commun. 2021;12:1786.33741974 10.1038/s41467-021-22024-3
112. Ling C Rönn T Epigenetics in human obesity and type 2 diabetes Cell Metab 2019 29 1028 1044 10.1016/j.cmet.2019.03.009 30982733
Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 2019;29:1028–44.30982733 10.1016/j.cmet.2019.03.009
113. Shu F Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets Signal Transduct Target Ther 2023 8 32 10.1038/s41392-022-01300-8 36646695
Shu F, et al. Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets. Signal Transduct Target Ther. 2023;8:32.36646695 10.1038/s41392-022-01300-8
114. Yang M Luo H Yi X Wei X Jiang DS The epigenetic regulatory mechanisms of ferroptosis and its implications for biological processes and diseases MedComm 2023 4 3 e267 10.1002/mco2.267 37229485
Yang M, Luo H, Yi X, Wei X, Jiang DS. The epigenetic regulatory mechanisms of ferroptosis and its implications for biological processes and diseases. MedComm. 2023;4(3):e267.37229485 10.1002/mco2.267
115. Bai T Liang R Zhu R MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells J Cell Physiol 2020 235 7–8 5637 5648 10.1002/jcp.29496 31960438
Bai T, Liang R, Zhu R, et al. MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol. 2020;235(7–8):5637–48.31960438 10.1002/jcp.29496
116. Lu Y Chan YT Tan HY Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma J Exp Clin Cancer Res 2022 41 1 3 10.1186/s13046-021-02208-x 34980204
Lu Y, Chan YT, Tan HY, et al. Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41(1):3.34980204 10.1186/s13046-021-02208-x
117. Yang H Sun W Bi T ZNF8-miR-552-5p axis modulates ACSL4-mediated ferroptosis in hepatocellular carcinoma DNA Cell Biol 2023 42 6 336 347 10.1089/dna.2022.0582 37126948
Yang H, Sun W, Bi T, et al. ZNF8-miR-552-5p axis modulates ACSL4-mediated ferroptosis in hepatocellular carcinoma. DNA Cell Biol. 2023;42(6):336–47.37126948 10.1089/dna.2022.0582
118. Hu Z Zhang H Liu W Mechanism of HBV-positive liver cancer cell exosomal miR-142-3p by inducing ferroptosis of M1 macrophages to promote liver cancer progression Transl Cancer Res 2022 11 5 1173 1187 10.21037/tcr-22-96 35706810
Hu Z, Zhang H, Liu W, et al. Mechanism of HBV-positive liver cancer cell exosomal miR-142-3p by inducing ferroptosis of M1 macrophages to promote liver cancer progression. Transl Cancer Res. 2022;11(5):1173–87.35706810 10.21037/tcr-22-96
119. Hu Z Yin Y Jiang J Exosomal miR-142-3p secreted by hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) cells promotes ferroptosis of M1-type macrophages through SLC3A2 and the mechanism of HCC progression J Gastrointest Oncol 2022 13 2 754 767 10.21037/jgo-21-916 35557596
Hu Z, Yin Y, Jiang J, et al. Exosomal miR-142-3p secreted by hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) cells promotes ferroptosis of M1-type macrophages through SLC3A2 and the mechanism of HCC progression. J Gastrointest Oncol. 2022;13(2):754–67.35557596 10.21037/jgo-21-916
120. Hu Z Li L Li M miR-21-5p inhibits ferroptosis in hepatocellular carcinoma cells by regulating the AKT/mTOR signaling pathway through MELK J Immunol Res 2023 2023 8929525 10.1155/2023/8929525 37008632
Hu Z, Li L, Li M, et al. miR-21-5p inhibits ferroptosis in hepatocellular carcinoma cells by regulating the AKT/mTOR signaling pathway through MELK. J Immunol Res. 2023;2023:8929525.37008632 10.1155/2023/8929525
121. Sun J Liu Q Jiang Y Engineered small extracellular vesicles loaded with miR-654-5p promote ferroptosis by targeting HSPB1 to alleviate sorafenib resistance in hepatocellular carcinoma Cell Death Discov 2023 9 1 362 10.1038/s41420-023-01660-2 37777559
Sun J, Liu Q, Jiang Y, et al. Engineered small extracellular vesicles loaded with miR-654-5p promote ferroptosis by targeting HSPB1 to alleviate sorafenib resistance in hepatocellular carcinoma. Cell Death Discov. 2023;9(1):362.37777559 10.1038/s41420-023-01660-2
122. Xing K Bian X Shi D miR-612 enhances RSL3-induced ferroptosis of hepatocellular carcinoma cells via mevalonate pathway J Hepatocell Carcinoma 2023 10 2173 2185 10.2147/JHC.S433332 38084209
Xing K, Bian X, Shi D, et al. miR-612 enhances RSL3-induced ferroptosis of hepatocellular carcinoma cells via mevalonate pathway. J Hepatocell Carcinoma. 2023;10:2173–85.38084209 10.2147/JHC.S433332
123. Cao F Hao W Liang W Zeng H Zheng J MiR-339-5p inhibits ferroptosis by promoting autophagic degradation of FTH1 through targeting ATG7 in liver cancer cells Clin Med Insights Oncol 2024 18 11795549241244783 10.1177/11795549241244783 38628842
Cao F, Hao W, Liang W, Zeng H, Zheng J. MiR-339-5p inhibits ferroptosis by promoting autophagic degradation of FTH1 through targeting ATG7 in liver cancer cells. Clin Med Insights Oncol. 2024;18:11795549241244784.38628842 10.1177/11795549241244783
124. Liu M Hu M Liu R Wang L Wang J Wang Y Zhang R Wang H Liu M Zhang Y Wang L Pei W Zhang Y Unveiling the role of APOM gene in liver cancer: Investigating the impact of hsa-miR-4489/MUC1-mediated ferroptosis on the advancement of hepatocellular carcinoma cells Gene 2024 925 148591 10.1016/j.gene.2024.148591 38788818
Liu M, Hu M, Liu R, Wang L, Wang J, Wang Y, Zhang R, Wang H, Liu M, Zhang Y, Wang L, Pei W, Zhang Y. Unveiling the role of APOM gene in liver cancer: Investigating the impact of hsa-miR-4489/MUC1-mediated ferroptosis on the advancement of hepatocellular carcinoma cells. Gene. 2024;925:148591.38788818 10.1016/j.gene.2024.148591
125. Zhu S Zhang Q Sun X Zeh HJ 3rd Lotze MT Kang R HSPA5 regulates ferroptotic cell death in cancer cells Cancer Res 2017 77 2064 2077 10.1158/0008-5472.CAN-16-1979 28130223
Zhu S, Zhang Q, Sun X, Zeh HJ 3rd, Lotze MT, Kang R, et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 2017;77:2064–77.28130223 10.1158/0008-5472.CAN-16-1979
126. He F Zhang P Liu J Wang R Kaufman RJ Yaden BC ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis J Hepatol 2023 79 362 377 10.1016/j.jhep.2023.03.016 36996941
He F, Zhang P, Liu J, Wang R, Kaufman RJ, Yaden BC, et al. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis. J Hepatol. 2023;79:362–77.36996941 10.1016/j.jhep.2023.03.016
127. Shi Z Li Z Jin B Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation Clin Transl Med 2023 13 6 e1300 10.1002/ctm2.1300 37337470
Shi Z, Li Z, Jin B, et al. Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation. Clin Transl Med. 2023;13(6):e1300.37337470 10.1002/ctm2.1300
128. Chen F Wang L Long noncoding RNA CASC11 suppresses sorafenib-triggered ferroptosis via stabilizing SLC7A11 mRNA in hepatocellular carcinoma cells Discov Oncol 2023 14 1 145 10.1007/s12672-023-00761-9 37552314
Chen F, Wang L. Long noncoding RNA CASC11 suppresses sorafenib-triggered ferroptosis via stabilizing SLC7A11 mRNA in hepatocellular carcinoma cells. Discov Oncol. 2023;14(1):145.37552314 10.1007/s12672-023-00761-9
129. Yuan X Wang Y Jiao S Identification of SLC7A11-AS1/SLC7A11 pair as a ferroptosis-related therapeutic target for hepatocellular carcinoma J Cell Mol Med 2024 28 13 e18496 10.1111/jcmm.18496 38984939
Yuan X, Wang Y, Jiao S, et al. Identification of SLC7A11-AS1/SLC7A11 pair as a ferroptosis-related therapeutic target for hepatocellular carcinoma. J Cell Mol Med. 2024;28(13):e18496.38984939 10.1111/jcmm.18496
130. Zhang B Bao W Zhang S LncRNA HEPFAL accelerates ferroptosis in hepatocellular carcinoma by regulating SLC7A11 ubiquitination Cell Death Dis 2022 13 8 734 10.1038/s41419-022-05173-1 36008384
Zhang B, Bao W, Zhang S, et al. LncRNA HEPFAL accelerates ferroptosis in hepatocellular carcinoma by regulating SLC7A11 ubiquitination. Cell Death Dis. 2022;13(8):734.36008384 10.1038/s41419-022-05173-1
131. Zong K Lin C Luo K Ferroptosis-related lncRNA NRAV affects the prognosis of hepatocellular carcinoma via the miR-375-3P/SLC7A11 axis BMC Cancer 2024 24 1 496 10.1186/s12885-024-12265-y 38637761
Zong K, Lin C, Luo K, et al. Ferroptosis-related lncRNA NRAV affects the prognosis of hepatocellular carcinoma via the miR-375-3P/SLC7A11 axis. BMC Cancer. 2024;24(1):496.38637761 10.1186/s12885-024-12265-y
132. He GN Bao NR Wang S Ketamine induces ferroptosis of liver cancer cells by targeting lncRNA PVT1/miR-214-3p/GPX4 Drug Des Devel Ther 2021 15 3965 3978 10.2147/DDDT.S332847 34566408
He GN, Bao NR, Wang S, et al. Ketamine induces ferroptosis of liver cancer cells by targeting lncRNA PVT1/miR-214-3p/GPX4. Drug Des Devel Ther. 2021;15:3965–78.34566408 10.2147/DDDT.S332847
133. Kang X Huo Y Jia S He F Li H Zhou Q Chang N Liu D Li R Hu Y Zhang P Xu A Silenced LINC01134 enhances oxaliplatin sensitivity by facilitating ferroptosis through GPX4 in hepatocarcinoma Front Oncol 2022 12 939605 10.3389/fonc.2022.939605 35875091
Kang X, Huo Y, Jia S, He F, Li H, Zhou Q, Chang N, Liu D, Li R, Hu Y, Zhang P, Xu A. Silenced LINC01134 enhances oxaliplatin sensitivity by facilitating ferroptosis through GPX4 in hepatocarcinoma. Front Oncol. 2022;12:939605.35875091 10.3389/fonc.2022.939605
134. Li X Li Y Lian P Silencing lncRNA HCG18 regulates GPX4-inhibited ferroptosis by adsorbing miR-450b-5p to avert sorafenib resistance in hepatocellular carcinoma Hum Exp Toxicol 2023 42 9603271221142818 10.1177/09603271221142818 36786348
Li X, Li Y, Lian P, et al. Silencing lncRNA HCG18 regulates GPX4-inhibited ferroptosis by adsorbing miR-450b-5p to avert sorafenib resistance in hepatocellular carcinoma. Hum Exp Toxicol. 2023;42:9603271221142818.36786348 10.1177/09603271221142818
135. Li J Li Y Wang D Liao R Wu Z PLAG1 interacts with GPX4 to conquer vulnerability to sorafenib induced ferroptosis through a PVT1/miR-195-5p axis-dependent manner in hepatocellular carcinoma J Exp Clin Cancer Res 2024 43 1 143 10.1186/s13046-024-03061-4 38745179
Li J, Li Y, Wang D, Liao R, Wu Z. PLAG1 interacts with GPX4 to conquer vulnerability to sorafenib induced ferroptosis through a PVT1/miR-195-5p axis-dependent manner in hepatocellular carcinoma. J Exp Clin Cancer Res. 2024;43(1):143.38745179 10.1186/s13046-024-03061-4
136. Yuan J Lv T Yang J HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma Redox Biol 2022 58 102546 10.1016/j.redox.2022.102546 36423520
Yuan J, Lv T, Yang J, et al. HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma. Redox Biol. 2022;58:102546.36423520 10.1016/j.redox.2022.102546
137. Gao Y Tong M Wong TL Ng KY Xie YN Wang Z Yu H Loh JJ Li M Ma S Long noncoding RNA URB1-antisense RNA 1 (AS1) suppresses sorafenib-induced ferroptosis in hepatocellular carcinoma by driving ferritin phase separation ACS Nano 2023 17 22240 22258 10.1021/acsnano.3c01199 37966480
Gao Y, Tong M, Wong TL, Ng KY, Xie YN, Wang Z, Yu H, Loh JJ, Li M, Ma S. Long noncoding RNA URB1-antisense RNA 1 (AS1) suppresses sorafenib-induced ferroptosis in hepatocellular carcinoma by driving ferritin phase separation. ACS Nano. 2023;17:22240–58.37966480 10.1021/acsnano.3c01199
138. Zhou L Zhang Q Cheng J LncRNA SNHG1 upregulates FANCD2 and G6PD to suppress ferroptosis by sponging miR-199a-5p/3p in hepatocellular carcinoma Drug Discov Ther 2023 17 4 248 256 10.5582/ddt.2023.01035 37599085
Zhou L, Zhang Q, Cheng J, et al. LncRNA SNHG1 upregulates FANCD2 and G6PD to suppress ferroptosis by sponging miR-199a-5p/3p in hepatocellular carcinoma. Drug Discov Ther. 2023;17(4):248–56.37599085 10.5582/ddt.2023.01035
139. Qi W Li Z Xia L LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells Sci Rep 2019 9 1 16185 10.1038/s41598-019-52837-8 31700067
Qi W, Li Z, Xia L, et al. LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells. Sci Rep. 2019;9(1):16185.31700067 10.1038/s41598-019-52837-8
140. Zhang Y Luo M Cui X Long noncoding RNA NEAT1 promotes ferroptosis by modulating the miR-362-3p/MIOX axis as a ceRNA Cell Death Differ 2022 29 9 1850 1863 10.1038/s41418-022-00970-9 35338333
Zhang Y, Luo M, Cui X, et al. Long noncoding RNA NEAT1 promotes ferroptosis by modulating the miR-362-3p/MIOX axis as a ceRNA. Cell Death Differ. 2022;29(9):1850–63.35338333 10.1038/s41418-022-00970-9
141. Guan L Wang F Wang M Downregulation of HULC induces ferroptosis in hepatocellular carcinoma via targeting of the miR-3200-5p/ATF4 Axis Oxid Med Cell Longev 2022 2022 9613095 10.1155/2022/9613095 35615577
Guan L, Wang F, Wang M, et al. Downregulation of HULC induces ferroptosis in hepatocellular carcinoma via targeting of the miR-3200-5p/ATF4 Axis. Oxid Med Cell Longev. 2022;2022:9613095.35615577 10.1155/2022/9613095
142. Man Q Zhang G Chen X EPS15-AS1 Inhibits AKR1B1 Expression to Enhance Ferroptosis in Hepatocellular Carcinoma Cells J Cancer 2024 15 4 1030 1040 10.7150/jca.89993 38230218
Man Q, Zhang G, Chen X, et al. EPS15-AS1 Inhibits AKR1B1 Expression to Enhance Ferroptosis in Hepatocellular Carcinoma Cells. J Cancer. 2024;15(4):1030–40.38230218 10.7150/jca.89993
143. Chen F Li M Wang L LncRNA CASC11 promotes hepatocellular carcinoma progression via upregulation of UBE2T in a m(6)A-dependent manner Front Oncol 2021 11 772671 10.3389/fonc.2021.772671 34900723
Chen F, Li M, Wang L. LncRNA CASC11 promotes hepatocellular carcinoma progression via upregulation of UBE2T in a m(6)A-dependent manner. Front Oncol. 2021;11:772671.34900723 10.3389/fonc.2021.772671
144. Xu Q Zhou L Yang G CircIL4R facilitates the tumorigenesis and inhibits ferroptosis in hepatocellular carcinoma by regulating the miR-541-3p/GPX4 axis Cell Biol Int 2020 44 11 2344 2356 10.1002/cbin.11444 32808701
Xu Q, Zhou L, Yang G, et al. CircIL4R facilitates the tumorigenesis and inhibits ferroptosis in hepatocellular carcinoma by regulating the miR-541-3p/GPX4 axis. Cell Biol Int. 2020;44(11):2344–56.32808701 10.1002/cbin.11444
145. Zhai H Zhong S Wu R Suppressing circIDE/miR-19b-3p/RBMS1 axis exhibits promoting-tumour activity through upregulating GPX4 to diminish ferroptosis in hepatocellular carcinoma Epigenetics 2023 18 1 2192438 10.1080/15592294.2023.2192438 36989117
Zhai H, Zhong S, Wu R, et al. Suppressing circIDE/miR-19b-3p/RBMS1 axis exhibits promoting-tumour activity through upregulating GPX4 to diminish ferroptosis in hepatocellular carcinoma. Epigenetics. 2023;18(1):2192438.36989117 10.1080/15592294.2023.2192438
146. Bi T Lu Q Pan X circFAM134B is a key factor regulating reticulophagy-mediated ferroptosis in hepatocellular carcinoma Cell Cycle 2023 22 17 1900 1920 10.1080/15384101.2023.2249302 37603831
Bi T, Lu Q, Pan X, et al. circFAM134B is a key factor regulating reticulophagy-mediated ferroptosis in hepatocellular carcinoma. Cell Cycle. 2023;22(17):1900–20.37603831 10.1080/15384101.2023.2249302
147. Tan YR Jiang BH Feng WJ Circ0060467 sponges miR-6805 to promote hepatocellular carcinoma progression through regulating AIFM2 and GPX4 expression Aging (Albany NY) 2024 16 2 1796 1807 10.18632/aging.205460 38244593
Tan YR, Jiang BH, Feng WJ, et al. Circ0060467 sponges miR-6805 to promote hepatocellular carcinoma progression through regulating AIFM2 and GPX4 expression. Aging (Albany NY). 2024;16(2):1796–807.38244593 10.18632/aging.205460
148. Liu Y Li J Circular RNA 0016142 knockdown induces ferroptosis in hepatocellular carcinoma cells via modulation of the MicroRNA-188-3p/glutathione peroxidase 4 axis Biochem Genet 2024 62 1 333 351 10.1007/s10528-023-10417-6 37344692
Liu Y, Li J. Circular RNA 0016142 knockdown induces ferroptosis in hepatocellular carcinoma cells via modulation of the MicroRNA-188-3p/glutathione peroxidase 4 axis. Biochem Genet. 2024;62(1):333–51.37344692 10.1007/s10528-023-10417-6
149. Lyu N Zeng Y Kong Y Ferroptosis is involved in the progression of hepatocellular carcinoma through the circ0097009/miR-1261/SLC7A11 axis Ann Transl Med 2021 9 8 675 10.21037/atm-21-997 33987373
Lyu N, Zeng Y, Kong Y, et al. Ferroptosis is involved in the progression of hepatocellular carcinoma through the circ0097009/miR-1261/SLC7A11 axis. Ann Transl Med. 2021;9(8):675.33987373 10.21037/atm-21-997
150. Dong FL Xu ZZ Wang YQ Li T Wang X Li J Exosome-derived circUPF2 enhances resistance to targeted therapy by redeploying ferroptosis sensitivity in hepatocellular carcinoma J Nanobiotechnology 2024 22 298 10.1186/s12951-024-02582-6 38811968
Dong FL, Xu ZZ, Wang YQ, Li T, Wang X, Li J. Exosome-derived circUPF2 enhances resistance to targeted therapy by redeploying ferroptosis sensitivity in hepatocellular carcinoma. J Nanobiotechnology. 2024;22:298.38811968 10.1186/s12951-024-02582-6
151. Zhang XY Li SS Gu YR CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis Mol Cancer 2024 23 1 113 10.1186/s12943-024-02030-x 38802795
Zhang XY, Li SS, Gu YR, et al. CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis. Mol Cancer. 2024;23(1):113.38802795 10.1186/s12943-024-02030-x
152. Liu Z Wang Q Wang X Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5 Cell Death Discov 2020 6 72 10.1038/s41420-020-00306-x 32802409
Liu Z, Wang Q, Wang X, et al. Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5. Cell Death Discov. 2020;6:72.32802409 10.1038/s41420-020-00306-x
153. Zhang Q Fan X Zhang X Ju S Ferroptosis in tumors and its relationship to other programmed cell death: role of non-coding RNAs J Transl Med 2023 21 514 10.1186/s12967-023-04370-6 37516888
Zhang Q, Fan X, Zhang X, Ju S. Ferroptosis in tumors and its relationship to other programmed cell death: role of non-coding RNAs. J Transl Med. 2023;21:514.37516888 10.1186/s12967-023-04370-6
154. Winkle M El-Daly SM Fabbri M Calin GA Noncoding RNA therapeutics—challenges and potential solutions Nat Rev Drug Discov 2021 20 629 651 10.1038/s41573-021-00219-z 34145432
Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics—challenges and potential solutions. Nat Rev Drug Discov. 2021;20:629–51.34145432 10.1038/s41573-021-00219-z
155. Nappi F Non-coding RNA-targeted therapy: a state-of-the-art review Int J Mol Sci 2024 25 3630 10.3390/ijms25073630 38612441
Nappi F. Non-coding RNA-targeted therapy: a state-of-the-art review. Int J Mol Sci. 2024;25:3630.38612441 10.3390/ijms25073630
156. He AT Liu J Li F Yang BB Targeting circular RNAs as a therapeutic approach: current strategies and challenges Signal Transduct Target Ther 2021 6 1 185 10.1038/s41392-021-00569-5 34016945
He AT, Liu J, Li F, Yang BB. Targeting circular RNAs as a therapeutic approach: current strategies and challenges. Signal Transduct Target Ther. 2021;6(1):185.34016945 10.1038/s41392-021-00569-5
157. Zhao R Fu J Zhu L Chen Y Liu B Designing strategies of small-molecule compounds for modulating non-coding RNAs in cancer therapy J Hematol Oncol 2022 15 1 14 10.1186/s13045-022-01230-6 35123522
Zhao R, Fu J, Zhu L, Chen Y, Liu B. Designing strategies of small-molecule compounds for modulating non-coding RNAs in cancer therapy. J Hematol Oncol. 2022;15(1):14.35123522 10.1186/s13045-022-01230-6
158. Ma X Xu M Zhang X Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR-1291/FOXA2 and AMPKα/SLC7A11/GPX4 axis in colorectal cancer Cell Biol Int 2023 47 11 1813 1824 10.1002/cbin.12072 37471707
Ma X, Xu M, Zhang X, et al. Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR-1291/FOXA2 and AMPKα/SLC7A11/GPX4 axis in colorectal cancer. Cell Biol Int. 2023;47(11):1813–24.37471707 10.1002/cbin.12072
159. Huang J Deng C Guo T Cinobufotalin induces ferroptosis to suppress lung cancer cell growth by lncRNA LINC00597/hsa-miR-367-3p/TFRC pathway via resibufogenin Anticancer Agents Med Chem 2023 23 6 717 725 10.2174/1871520622666221010092922 36221890
Huang J, Deng C, Guo T, et al. Cinobufotalin induces ferroptosis to suppress lung cancer cell growth by lncRNA LINC00597/hsa-miR-367-3p/TFRC pathway via resibufogenin. Anticancer Agents Med Chem. 2023;23(6):717–25.36221890 10.2174/1871520622666221010092922
160. Gao X Wang XL Dexmedetomidine promotes ferroptotic cell death in gastric cancer via hsa_circ_0008035/miR-302a/E2F7 axis Kaohsiung J Med Sci 2023 39 4 390 403 10.1002/kjm2.12650 36718915
Gao X, Wang XL. Dexmedetomidine promotes ferroptotic cell death in gastric cancer via hsa_circ_0008035/miR-302a/E2F7 axis. Kaohsiung J Med Sci. 2023;39(4):390–403.36718915 10.1002/kjm2.12650
