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Ferroptosis: insight into the treatment of hepatocellular carcinoma

Cancer Cell International volume 24, Article number: 376 (2024) Cite this article

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignances in the world, with high morbidity and mortality. Due to the hidden onset of symptoms, there are huge obstacles in early diagnosis, recurrence, metastasis and drug resistance. Although great strides have been made in the treatment of HCC, effective treatment options are still limited and achieving longer survival for patients remains urgent. Ferroptosis is a novel type of programmed cell death that is mainly caused by iron-dependent oxidative damage. With further investigations, ferroptosis has been proved to be associated with the occurrence and development of various tumors. This article reviews the regulatory mechanism and signal transduction pathways of ferroptosis, investigates the complex relationship between autophagy, sorafenib resistance and immunotherapy with ferroptosis involved in HCC, providing new ideas and directions for the treatment of HCC.

Introduction

With the development of aging population, urbanization and industrialization, the incidence of cancer is increasing year by year. GLOBOCAN revealed that primary liver cancer was the sixth most common cancer and the third leading cause of cancer death worldwide in 2020, with about 906,000 new cases and 830,000 deaths [1]. Among primary liver cancers, hepatocellular carcinoma (HCC) is the most common type, accounting for 75–85% of cases [2]. The selection of treatment methods for HCC is related to clinical and pathological stage, liver resection (LR), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), chemotherapy and radiotherapy are commonly used as treatment methods, in addition to liver transplantation (LT) [3]. HCC is a stealthy adversary, often beginning with a subtle onset but advancing swiftly,, which brings great challenges to people in terms of early diagnosis, recurrence, metastasis and drug resistance.

In recent years, with the emergence of the concept of “ferroptosis” [4], and the intensification of its research, ferroptosis has been expected to provide innovative approaches for cancer treatment. Ferroptosis is a novel type of programmed cell death, which can be induced by Erastin and RSL3, and is mainly caused by iron-dependent oxidative damage, distinguished from other cell death mechanisms including apoptosis, pyroptosis, autophagy and programmed necrosis [5]. When ferroptosis occurs, cellular integrity is compromised as the cell membrane disintegrates. It can be observed under an electron microscope that the mitochondria undergoing a reduction in size and an increase in the density of their double membranes, the mitochondrial cristae may diminish or vanish entirely, and the outer membrane may exhibit signs of shrinkage and fracturing [6]. Studies have confirmed the pivotal regulatory influence of ferroptosis in the genesis and progression of various malignancies, such as HCC, pancreatic cancer, breast cancer, prostate cancer [7,8,9,10], and it also associated with tumor recurrence and chemotherapy resistance [11, 12].

This article reviews the regulatory mechanism and research advancements of ferroptosis in HCC, aiming at enhancing our comprehension of the underlying mechanisms of tumorigenesis and progression, thereby offering novel perspectives for the clinical management of HCC in the future (Fig. 1).

Fig. 1
figure 1

Factors associated with ferroptosis in HCC

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Key regulatory pathways and factors

Studies have shown that in the regulatory pathway of ferroptosis in HCC, including a spectrum of tumor-associated genes, non-coding RNAs and other factors can exert rich and diverse effects on the progression of HCC.

System Xc− pathway

System Xc− is a cystine/glutamate antiporter situated on the cell membrane, responsible for the exchange of glutamate out of the extracellular and cystine into the intracellular in a ratio of 1:1. Cystine is formed by an enzymatic reaction to cysteine, which is then further reacted to synthesize glutathione (GSH) [13]. GSH serves as a vital antioxidant and free radical scavenger in the body, and peroxidase can reduce lipid peroxidation and reactive oxygen species (ROS) within cells [14]. System Xc− mainly consists of the light chain of SLC7A11 and the heavy chain of SLC3A2 in the solute carrier family, of which SLC7A11 has been found to be overexpressed in a variety of human cancers [15], and several regulatory factors in the system Xc− pathway that cause ferroptosis in HCC are also found to be related to SLC7A11. Furthermore, activating transcription factor 4 (ATF4) and nuclear factor erythroid 2-related factor 2 (NRF2) are two major transcription factors that mediate stress-induced transcription of SLC7A11 [16]. Cells with elevated NRF2 exhibited a remarkable increase of tumor proliferation, along with enhanced capabilities of migration and invasion [17].

Researches have also revealed that the tumor suppressor protein p53 repressed the uptake of cystine, thereby sensitizing cells to ferroptosis by inhibiting SLC7A11 expression [18]. It has been reported that the up-regulation of myo-inositol oxygenase (MIOX) promoted the production of ROS while the production of NADPH and GSH reduced [19], thereby decreased the antioxidant capacity of tumor cells. p53 increased the expression of lncRNA NEAT1 by binding to its promoter, competitively binding more miR-362-3p and releasing miR-362-3p-mediated MIOX inhibition, resulted in the enhanced ferroptosis sensitivity of hepatoma cells ultimately [20]. In addition, p53 activated the expression of PCDHB14 to decrease the expression of SLC7A11 by enhancing the degradation of p65 mediated by E3 ubiquitin ligase RNF182 to block p65 binding to the promoter of SLC7A11, which resulted in the increased sensitivity of ferroptosis and suppressed the progression of HCC [21]. The Ser46 phosphorylation of p53, which was inhibited by ZNF498, a zinc finger protein with high expression in HCC, was reported to restain the apoptosis and ferroptosis of HCC [22].

BRCA1-associated protein 1 (BAP1) is the product of histone 2A mono-ubiquitination (H2Aub) at lysine-119 on SLC7A11 [23], which could repress the expression of SLC7A11 by diminishing H2A ubiquitination on the SLC7A11 promoter, which was independent of the influence of p53, NRF2 and ATF4 [24]. Additionally, over-expression of suppressor of cytokine signaling 2 (SOCS2) has been shown to augment the radiosensitivity of HCC by promoting the ubiquitination and degradation of SLC7A11 [25]. The ubiquitin specific peptidase 8 (USP8), which was found to favor HCC progression, inhibited the O-GlcNAcylation of SLC7A11 to stabilize its expression, thus facilitating the ferroptosis of HCC [26, 27].

C8orf76 has been confirmed to be associated with the occurrence and metastasis of gastric cancer [28], and its elevated expression also predicted poor prognosis of breast cancer [29]. Li et al. found that the upregulation of C8orf76 in HCC binded to the promoter region and transcriptionally up-regulated the expression of SLC7A11, thus inhibiting lipid peroxidation and accelerating tumor growth [30].

TEA domain (TEAD) proteins comprise a family of transcription factors that regulate the expression of various genes involved in cell proliferation, differentiation, and apoptosis [31]. Evidence has indicated that YAP/TAZ, a co-activated transcription factor, upregulated the expression of SLC7A11 in a TEAD-dependent manner and maintaining the protein stability, nuclear localization and transcriptional activity of ATF4 cooperately, resulting in the prevention of ferroptosis in HCC [32]. Concurrently, the overexpression of lipoxygenase ALOXE3, a target gene of YAP-TEAD, effectively increased the susceptibility of hepatoma cells to ferroptosis [33].

Transforming growth factor β1 (TGF-β1) has been found to promote ferroptosis of hepatoma cells by inhibiting SLC7A11 [34], while branched-chain amino acid aminotransferase 2 (BCAT2), as a key enzyme mediating the metabolism of sulfur-containing amino acids, could specifically antagonize the inhibitory effect of system Xc− and protect HCC from ferroptosis by modulating the intracellular glutamate level [35]. Moreover, Shan et al. have validated the involvement of centrosomal protein 290 (CEP290) in the ferroptosis of HCC via modulating NRF2 signaling pathway [36], while adiponectin receptor 1 (AdipoR1) has been shown to govern the induction of radiotherapy-induced ferroptosis in hepatoma cells through the NRF2-Xc− pathway [37]. Quiescin sulfhydryl oxidase 1 (QSOX1) was a cellular pro-oxidant that inhibited the activity of NRF2 by promoting ubiquitination-mediated EGFR degradation and accelerating its endosomal transport within cells [38]. Sigma-1 receptor (S1R) serves as a protein regulator that modulates ROS accumulation through NRF2 to confer protection to HCC from ferroptosis [39].

GPX4 in HCC with ferroptosis

Glutathione peroxidative 4 (GPX4) is a central cytoprotective factor downstream of system Xc− [40]. The overexpression of GPX4 predicted a poor prognosis of HCC patients by shielding cells from oxidative stress and reducing intracellular ROS levels, thereby promoting the proliferation, migration, angiogenesis and immune cell penetration of tumor cells [41, 42].

It has been found that circIL4R was up-regulated in HCC tissues and cell lines, which targeted GPX4 through miR-541-3p, thus inhibiting ferroptosis and promoting the progression of HCC [43]. The absence of phosphoseryl-tRNA kinase (PSTK) could lead to the inactivation of GPX4, then blocked GSH metabolism and increased the sensitivity of hepatoma cells to chemotherapy [44]. Glutathione S-transferase zeta 1 (GSTZ1) was an enzyme in phenylalanine catabolism, and known to suppress the expression of NRF2 [45]. GSTZ1-1 deficiency led to succinylacetone accumulation, alkylation modification of Kelch-like ECH-associated protein 1 (Keap1), thus resulting in NRF2 activation and GPX4 upregulation to promote the progression of HCC [46, 47]. Feng et al. have demonstrated that the silencing of SEH1 like nucleoporin (SEH1L) could trigger ferroptosis and impede the progression of HCC through the ATF3/HMOX1/GPX4 axis [48].

Furthermore, CHAC1 recognized as a critical gene for GSH degradation, has been correlated with an adverse poor tumor prognosis [49], while dihydroartemisinin could promote the up-regulation of CHAC1 expression induced by the reaction with unfolded protein, reducing GSH synthesis and down-regulating GPX4 expression in hepatoma cells, then promoting ferroptosis in HCC [50].

Lipid peroxidation

Glucose-6-phosphate dehydrogenase (G6PD) functions as a rate-limiting enzyme in the pentose phosphate pathway (PPP), in which ribose-5-phosphate and NADPH are produced to foster tumor growth. A study has illuminated that G6PD could enhance the invasive and migratory capabilities of hepatoma cells by inducing epithelial-mesenchymal transition (EMT) via signal transducer and activator of transcription 3 (STAT3) pathway [51]. Zou et al. have uncovered that P450 oxidoreductase (POR) promoted ferroptosis by peroxidation of membrane polyunsaturated phospholipids [52], while G6PD deficiency could inhibit cell growth, metastasis and tumor occurrence by up-regulating POR [53]. Li et al. have confirmed that polyunsaturated fatty acids (PUFAs) were particularly susceptible to be oxidized when ferroptosis occurred, resulting in the destruction of lipid bilayer and affecting the function of cell membrane. Biosynthesis of PUFAs in cell membranes and maintenance of normal physiological functions required a series of enzymes, such as ACSL4 and LPCAT3, to ensure cell membranes remain intact [54]. High-density lipoprotein-binding protein (HDLBP) was an important transporter to protect cells from excessive cholesterol accumulation, and its expression was increased in HCC tissues. HDLBP has the capacity to modulate the ubiquitination of ferroptosis suppressor protein 1 (FSP1) through stabilizing lncFAL, thereby inhibiting ferroptosis in HCC [55]. As a component of the complement system, Ficolin 3 has been found to exhibit significantly diminished expression in HCC, and this reduction leaded to the accumulation of monounsaturated fatty acid (MUFA), and promoted ferroptosis resistance [56].

In addition, studies have indicated that glutamine synthase 2 (GLS2) promoted the production of α-ketoglutaric acid via glutamate, thereby increasing lipid ROS and propelling ferroptosis in HCC [57]. Erastin, known as an ferroptosis inducer, up-regulated lncRNA Gabpb1-AS1, but down-regulated GABPB1 protein levels by blocking GABPB1 translation, resulting in decreased expression of PRDX5 peroxidase gene. Subsequently, this chain of events culminated in a swift accumulation of ROS within HepG2 cells, ultimately impairing the cells’ antioxidant defenses [58].

Non-coding RNAs

There are a vast array of non-coding RNAs in the body, and a growing number of studies have demonstrated that they can affect numerous molecular targets and act as oncogenes or tumor suppressors [59]. In recent years, the spotlight in oncology research has focused on micro RNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) [60].

It has revealed that circ0097009 was markedly overexpressed in HCC and sponged with miR-1261 competively to enhance the expression of SLC7A11, while inhibition of circ0097009 exhibited an opposite effect [61]. LncRNA HULC has been identified to modulate the activity of ATF4 by interacting with miR-3200-5P [62], thereby participating in the regulation process of ferroptosis in hepatoma cells. The expression of lncRNA HEPFAL was confirmed to be lower in HCC tissues than in normal liver tissues. Moreover, in vitro and in vivo experiments have corroborated that lncRNA HEPFAL could reduce the migration and invasion of hepatoma cells, as well as ferroptosis promotion by regulating SLC7A11 ubiquitination [63]. Zhai et al. have discovered that the expression of RBMS1 was down-regulated in HCC, which was associated with poor survival of HCC patients. The inhibition of the circIDE/miR-19b-3p/RBMS1 axis could up-regulate GPX4 and favor tumor growth [64]. Additionally, circPIAS1 inhibited ferroptosis and promoted HCC progression through the miR-455-3p/NUPR1/FTH1 axis [65].

N6-methyladenosine (m6A) refers to the methylation modification of the sixth nitrogen atom on adenine on RNA, which is the most common epigenetic modification in all RNAs including mRNA and non-coding RNA [66, 67]. The m6A modification showed a close involvment in the occurrence and development of human malignancies [68]. Methyltransferase-like 14 (METTL14) induced m6A modification in the 5’ non-coding region of SLC7A11 through YTHDF2-dependent pathway, resulting in the degradation of SLC7A11 and ferroptosis promotion in HCC [69]. Another m6A methylase, METTL9, was also found to faciliate HCC progression through SLC7A11 [70]. In addition, the methylase WTAP confered the m6A modification on circCMTM3 was reported to inhibite ferroptosis in HCC by recruiting IGF2BP1 to increase the stability of PARK7 [71].

Autophagy-related pathways and factors in ferroptosis

Autophagy is a ubiquitous self-protection mechanism in eukaryotic cells, which can facilitate cellular metabolism and maintain cell homeostasis by degrading damaged organelles, proteins and lipids in a lysosomal dependent manner to renew cells’ energy. Autophagy plays a crucial role in the process of cell survival and death [72]. It has been shown that autophagy played a dynamic role in inhibiting or promoting tumor through oxidative stress in different backgrounds and stages of tumor development [73, 74]. Recent studies have found that the activation of autophagy can induce ferroptosis through a variety of molecular mechanisms, and it is more believed that ferroptosis is actually an autophagic cell death regulated by a series of crosstalk proteins between autophagy and ferroptosis.

p62 is a multifunctional protein related to autophagy, Wu et al. have confirmed that p62 directly inhibited Keap1 under physiological conditions to activate NRF2 and then protect hepatoma cells from ferroptosis [75, 76]. Zhang et al. have found that RNA binding protein ZFP36/TTP prevented ferroptosis by regulating the autophagy signaling pathway of hepatic stellate cells. Its overexpression could lead to the decline of ATG16L1 mRNA by combining with AU-rich elements (AREs) in the 3’-untranslated region (3’-UTR), triggered autophagy inactivation and prevented the degradation of autophagy ferritin, ultimately leading to ferroptosis resistance [77]. BECN1 was another key regulator of autophagy [78], which have been shown to bind with SLC7A11 to promote ferroptosis in HCC [79].

The great success of all-trans-retinoic acid (ATRA) in the differentiated treatment of acute promyelocytic leukemia (APL) not only improved the prognosis of APL, but also facilitated the study of ATRA in the treatment of other tumors [80]. Fang et al. have discovered that ATRA induced autophagy through the Bcl-2/BECN1 pathway, meanwhile, ATRA induced autophagy participated in the inhibition of malignant behavior of hepatoma cells by reversing the EMT process [81]. In addition, Sun et al. have demonstrated that ATRA inhibited the transport of glutamate and cystine, and the reduction of raw material inhibited GSH synthesis, thus promoting ferroptosis in hepatoma cells [82].

Rapamycin is an inducer of autophagy, and mammalian target of rapamycin (mTOR) has been found to be associated with ferroptosis of tumor cells in several studies [83,84,85]. Huang et al. have found that MCF2L was highly expressed in HCC tissues, and the down-regulation of MCF2L promoted ferroptosis in hepatoma cells through the PI3K/mTOR pathway [86]. MiR-21-5p and maternal embryonic leucine zipper kinase (MELK) were highly expressed in HCC, and their overexpression could promote EMT of HCC cells. It was also confirmed that miR-21-5p targeted MELK and inhibited ferroptosis by regulating AKT/mTOR signaling pathway, thereby promoting the development of HCC [87]. Tribble, a member of the CAMK Ser/Thr protein kinase family, performed its biological functions through direct interaction with AKT proteins to regulate cell proliferation, apoptosis, and differentiation [88]. Ubiquitin (Ub) was required for ubiquitination and subsequent degradation of GPX4, tribbles homolog 2 (TRIB2) mitigated the effects of oxidative damage by reducing the availability of Ub, enabling exclusive manipulation of RSL3 and Erastin induced ferroptosis independent of GPX4 and GSH [89].

As a selective autophagy method, ferritinophagy mediated ferritin degradation and released of free iron to participate in the regulation of intracellular iron content. Moderate ferritinophagy kept iron content stable, but excessive ferritinophagy released a lot of free iron. Nuclear receptor co-activator 4 (NCOA4) was considered to be a key regulatory factor of ferritinophagy, which was targeted to ferritin and delivered to lysosomes for degradation and release of free iron, and its mediated ferritinophagy constituted an important part of iron metabolism [90]. Recent studies have shown that NCOA4 was regulated by iron content, autophagy, lysosome, hypoxia and other factors, indicating that NCOA4-mediated ferritin degradation was related to ferroptosis [91] (Table 1).

Table 1 Autophagy-related pathways and factors of ferroptosis in HCC
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The mechanism of ferroptosis and sorafenib resistance

Sorafenib is a multi-targeted tyrosine kinase inhibitor approved by the FDA for the systemic treatment of advanced HCC, which exhibits anti-tumor effects by suppressing tumor proliferation and angiogenesis to prolong the median overall survival of patients with advanced HCC [92]. However, the resistance of sorafenib makes it difficult for HCC patients to benefit in the long term. Studies have found that sorafenib could induce ferroptosis in cells, indicating that ferroptosis was closely related to sorafenib resistance. The epigenetic biological modification, transport process and tumor microenvironment might be responsible for sorafenib resistance [93,94,95]. Moreover, an amount of studies have shown that additional induction of ferroptosis can significantly improve the efficacy of sorafenib, especially in sorafenib-resistant HCC cells [96].

The molecular mechanism of ferroptosis involved in sorafenib resistance were colorful and complex. DAZ-associated protein 1 (DAZAP1) is a highly conserved RNA binding protein (RBPs) [97] and has been found to be significantly up-regulated in HCC. The aberrant expression of DAZAP1 was positively correlated with larger tumor volume, high incidence of vascular invasion and poor prognosis of HCC patients. DAZAP1 has also been revealed to inhibit sorafenib induced ferroptosis by regulating SLC7A11 transcriptionally [98].

ATP-binding cassette (ABC) transporters constitute one of the largest families of membrane proteins in most organisms. Huang et al. have showed that the expression of ABCC5 was significantly induced in sorafenib-resistant hepatoma cells, and ABCC5 inhibited ferroptosis of hepatoma cells by stabilizing SLC7A11 protein to increase intracellular GSH content and reduce lipid peroxidation accumulation via PI3K/AKT/NRF2 axis [99]. Some studies have found that NRF2 signals promote the differentiation and migration of cancer stem cells and ABC transporter gene display ferroptosis suppression effect to acquire sorafenib resistance in hepatoma cells [100]. Metallothionein-1G (MT-1G) was identified as a novel transcriptional target of NRF2 with an up-regulation in HCC. Ferroptosis inhibition via lipid peroxidation regulation by MT-1G was unveiled to attribute to sorafenib-injury in HCC cells [101].

The transcription level of miR-23a-3p in sorafenib resistant cells was found to enhance in an ETS proto-oncogene 1 (ETS1) -dependent manner through ferroptosis inhibition by modulating cellular iron accumulation and lipid peroxidation via the ETS1/miR-23a-3p/ACSL4 axis [102]. In addition, IGF2BP3 has been shown to promote the stability of NRF2 mRNA by m6A modification and negatively regulate sorafenib-induced ferroptosis in hepatoma cells [103]. LncRNA HCG18 was confirmed to be highly expressed in HCC [104], and silencing lncRNA HCG18 regulated GPX4-mediated ferroptosis by sponging miR-450B-5P to reduce sorafenib resistance [105]. Highly expression of lncRNA DUXAP8 in HCC was indicated with sorafenib resistance and poor prognosis. And the palmitoylation of SLC7A11 was promoted by lncRNA DUXAP8 to prevent the lysosomal degradation of SLC7A11 to inhibit HCC ferroptosis [106].

In addition, fibronectin type III domain containing 5 (FNDC5) has been found to promote the nuclear translocation pathway of NRF2 by activating PI3K/AKT, enhancing intracellular antioxidant capacity and ultimately reducing sorafenib-induced ferroptosis [107]. PI3K/AKT is also a common pathway in autophagy [108], implying another crosstalk between autophagy and ferroptosis in the mechanism related to sorafenib resistance. For instance, Li et al. have found that CISD2 was highly expressed in hepatoma cells, and the inhibition of CISD2 promoted excessive accumulation of iron ions through autophagy to promote sorafenib-induced ferroptosis [109].

On the other hand, some researches have indicated that ferroptosis may promote sorafenib resistance. Sestrin2 (Sesn2), an antioxidant protein, has been upregulated by sorafenib-induced ferroptosis in a dose and time dependent manner [110]. Additionally, sorafenib effectively activated endoplasmic reticulum phagocytosis mediated by receptor protein FAM134B to reduce lipid peroxidation and thus maintain cell homeostasis [111]. Autophagy and the change of the tumor microenvironment may play a dual role under the background of ferroptosis and sorafenib, so the interplay between sorafenib and ferroptosis is intricate and profound investigation would be necessitated to demystify the phenomenon of sorafenib resistance and enhance the therapeutic implications (Table 2).

Table 2 Mechanisms of ferroptosis in HCC associated with sorafenib resistance
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Relationship between ferroptosis and tumor immune microenvironment

The immune component of tumor is referred to as tumor immune microenvironment (TIME), which exerts a multifaceted and crucial influence in tumor occurrence, development and chemotherapy resistance. Concurrently, immunotherapy for tumors is also a beneficial treatment modality for patients.

Macrophages are an important part of the TIME, which can be polarized in different directions under the action of different microenvironments and stimulating factors. Existing studies have shown that M1 macrophages can promote inflammation, kill pathogens and anti-tumor, while M2 macrophages can promote angiogenesis and tissue repair, and even promote tumor growth through immunosuppression [112]. Hao et al. have demonstrated that knockdown of APOC1 enhanced ferroptosis and induced the polarization of tumor-associated macrophages into M1 type through the pathways of lipid metabolism and iron metabolism, thereby inhibiting HCC [113]. Studies have shown that knockdown of SLC7A11 reduced the expression of phosphorylated STAT6 and PPAR-γ in macrophages, while enhancing the expression of SOCS3 and inhibiting the polarization of M2 macrophages. Moreover, SLC7A11-mediated ferroptosis of macrophages could increase the expression of PD-L1 in macrophages and improve the efficacy of anti-PD-L1 therapy [114]. And Huang et al. have found that transmembrane protein 147 (TMEM147) could inhibit ferroptosis and promote the polarization of M2 macrophages, thus promoting HCC progression [115]. Other studies have shown that mitochondrial translocator protein (TSPO) could inhibit ferroptosis of HCC cells through NRF2-mediated antioxidant defense system, and promote immune escape of HCC by up-regulating the expression of PD-L1 through NRF2-mediated transcription [116].

In addition, studies have found that FSP1 was significantly overexpressed in HCC and regulated by Keap1/NRF2, while iFSP1 (FSP1 inhibitor) can effectively reduce the burden of HCC and significantly increase the immune penetration including dendritic cells (DC), macrophages and T cells [117]. Li et al. have showed that MAT1A was low expressed in HCC, and its overexpression could promote ferroptosis of HCC cells by increasing the level of S-adenosylmethionine, increasing the cytotoxic effect of CD8 + T cells and interferon-γ production [118]. It has also been shown that in GPX4-deficient tumors, CD8 + T cells have increased IFN γ secretion, further manifested by T-cell-dependent upregulation of PD-L1 expression, suggesting that ferroptosis increases CD8 + T cell functional activation [119]. Zheng et al. have found that high expression of phosphoglycerate mutase 1 (PGAM1) in HCC was associated with poor prognosis and poor response to immunotherapy, while inhibition of PGAM1 played an anti-tumor role by promoting ferroptosis and CD8 + T cell infiltration to work synergistically with anti-PD-1 immunotherapy [120]. Additionally, MER proto-oncogene tyrosine kinase (MerTK) upregulated SLC7A11 through ERK/SP1 pathway to cause immunosuppressive TME by recruiting myeloid-derived suppressor cells (MDSCs), leading to anti-PD-1 /PD-L1 treatment resistance [121].

Summary and perspectives

It is difficult to diagnose HCC in the early stage, with high recurrence and metastasis rates and easy to be resistant to drugs. The existing diagnosis and treatment methods are still difficult to meet good expectations, and the lives of patients are still facing great threats. Therefore, seeking more efficient and accurate diagnosis and treatment are still the focus of research. With the introduction of the concept of “ferroptosis” and the deepening of the research on its relationship with diseases, more and more evidence showed that ferroptosis was involved in the occurrence and development of HCC. The treatment targeting ferroptosis related pathways is expected to provide a new and more potential treatment plan for traditional treatment. Combined with relevant studies in recent years, this article reviews the mechanism and progress of ferroptosis in HCC from four aspects: ferroptosis related pathways, the crosstalk between ferroptosis and autophagy, sorafenib resistance, and tumor immune microenvironment, in order to provide a theoretical basis for targeted ferroptosis therapy of HCC.

For example, high expression of SLC7A11 in cancer cells also implied glucose and glutamine dependence, which provided a potential metabolic vulnerability for targeted therapy of tumors with high SLC7A11 expression [122]. Ceruloplasmin (Cp) was a multicopper enzyme endowed with ferroxidase activity, and its knockout could promote the accumulation of intracellular iron and lipid ROS induced by Erastin and RSL3 [123], whereas copper metabolism MURR1 domain 10 (COMMD10) could bind to HIF1α in HCC to inhibit SlC7A11-mediated ferroptosis [124]. In addition, ENO1 recruited CNOT6 to accelerate the mRNA decay of iron regulatory protein 1 (IRP1) in cancer cells, resulting in inhibition of the expression of mitoferrin-1 (Mfrn1), then inhibited mitochondrial- induced ferroptosis [125]. Visible, there are still many factors regulate the process of ferroptosis through various channels.

Targeted ferroptosis is expected to overcome drug resistance in HCC. How to exploit the vulnerability of ferroptosis to make tumor cells more susceptible to death and how to combine drugs to improve the efficacy will be the focus of future research. Prior to 2017, sorafenib was the only FDA-approved treatment option for advanced HCC, and as research continues, more and more patients are benefiting from new targeted therapies.

Taking sorafenib as an example, as a multi-kinase inhibitor with a multitude of molecular targets, it has been confirmed to induce ferroptosis in various types of cancer. However, we cannot ignore that sorafenib can cause changes in numerous genes and signaling pathways, which subsequently affect the tumor microenvironment and lead to the observation of resistance to ferroptosis. In addition, alterations in the tumor microenvironment can also impact the effectiveness of immunotherapy. Therefore, in the future, when targeting ferroptosis for disease treatment, it is essential to thoroughly consider the interactions between mechanisms, monitor the changes in the tumor microenvironment during the treatment process, and actively foster the synergistic benefits that combination therapies can offer.

In conclusion, due to the involvement of ferroptosis in the resistance mechanism of HCC, further research and elaboration on it will help to develop targeted drugs, provide new application prospects for cancer targeted therapy and improve the prognosis of patients.

Data availability

No datasets were generated or analysed during the current study.

References

  1. 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(3):209–49.

    Article  PubMed  Google Scholar 

  2. Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021;134(7):783–91.

    Article  PubMed  Google Scholar 

  3. Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hepatol Int. 2019;13(2):125–37.

    Article  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gao W, Wang X, Zhou Y, Wang X, Yu Y. Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther. 2022;7(1):196.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang Y, Quan F, Cao Q, Lin Y, Yue C, Bi R, Cui X, Yang H, Yang Y, Birnbaumer L, et al. Quercetin alleviates acute kidney injury by inhibiting ferroptosis. J Adv Res. 2021;28:231–43.

    Article  CAS  PubMed  Google Scholar 

  7. Liu Y, Zhang X, Zhang J, Tan J, Li J, Song Z. Development and validation of a combined ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma. Front Cell Dev Biol. 2020;8:596679.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ye Z, Zhuo Q, Hu Q, Xu X, Mengqi L, Zhang Z, Xu W, Liu W, Fan G, Qin Y, et al. FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells. Redox Biol. 2021;38:101807.

    Article  CAS  PubMed  Google Scholar 

  9. Li H, Yang P, Wang J, Zhang J, Ma Q, Jiang Y, Wu Y, Han T, Xiang D. HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk. J Hematol Oncol. 2022;15(1):2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ghoochani A, Hsu EC, Aslan M, Rice MA, Nguyen HM, Brooks JD, Corey E, Paulmurugan R, Stoyanova T. Ferroptosis Inducers are a Novel Therapeutic Approach for Advanced prostate Cancer. Cancer Res. 2021;81(6):1583–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Luis G, Godfroid A, Nishiumi S, Cimino J, Blacher S, Maquoi E, Wery C, Collignon A, Longuespée R, Montero-Ruiz L, et al. Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and fatty acid biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence. Redox Biol. 2021;43:102006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bridges RJ, Natale NR, Patel SA. System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 2012;165(1):20–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Niu B, Liao K, Zhou Y, Wen T, Quan G, Pan X, Wu C. Application of glutathione depletion in cancer therapy: enhanced ROS-based therapy, ferroptosis, and chemotherapy. Biomaterials. 2021;277:121110.

    Article  CAS  PubMed  Google Scholar 

  15. Lin Y, Dong Y, Liu W, Fan X, Sun Y. Pan-cancer analyses confirmed the ferroptosis-related gene SLC7A11 as a Prognostic Biomarker for Cancer. Int J Gen Med. 2022;15:2501–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koppula P, Zhang Y, Shi J, Li W, Gan B. The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J Biol Chem. 2017;292(34):14240–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Iseda N, Itoh S, Yoshizumi T, Tomiyama T, Morinaga A, Yugawa K, Shimokawa M, Shimagaki T, Wang H, Kurihara T, et al. Impact of nuclear factor erythroid 2-Related factor 2 in Hepatocellular Carcinoma: Cancer Metabolism and Immune Status. Hepatol Commun. 2022;6(4):665–78.

    Article  CAS  PubMed  Google Scholar 

  18. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, Baer R, Gu W. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520(7545):57–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Deng F, Sharma I, Dai Y, Yang M, Kanwar YS. Myo-Inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule. J Clin Invest. 2019;129(11):5033–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang Y, Luo M, Cui X, O’Connell D, Yang Y. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu Y, Ouyang L, Mao C, Chen Y, Li T, Liu N, Wang Z, Lai W, Zhou Y, Cao Y, et al. PCDHB14 promotes ferroptosis and is a novel tumor suppressor in hepatocellular carcinoma. Oncogene. 2022;41(27):3570–83.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang X, Zheng Q, Yue X, Yuan Z, Ling J, Yuan Y, Liang Y, Sun A, Liu Y, Li H, et al. ZNF498 promotes hepatocellular carcinogenesis by suppressing p53-mediated apoptosis and ferroptosis via the attenuation of p53 Ser46 phosphorylation. J Exp Clin Cancer Res. 2022;41(1):79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jyotsana N, Ta KT, DelGiorno KE. The role of Cystine/Glutamate Antiporter SLC7A11/xCT in the pathophysiology of Cancer. Front Oncol. 2022;12:858462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang Y, Koppula P, Gan B. Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1. Cell Cycle. 2019;18(8):773–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen Q, Zheng W, Guan J, Liu H, Dan Y, Zhu L, Song Y, Zhou Y, Zhao X, Zhang Y, et al. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death Differ. 2023;30(1):137–51.

    Article  CAS  PubMed  Google Scholar 

  26. Tang J, Long G, Hu K, Xiao D, Liu S, Xiao L, Zhou L, Tao Y. Targeting USP8 inhibits O-GlcNAcylation of SLC7A11 to promote Ferroptosis of Hepatocellular Carcinoma via stabilization of OGT. Adv Sci (Weinh). 2023;10(33):e2302953.

    Article  PubMed  Google Scholar 

  27. Tang J, Long G, Xiao L, Zhou L. USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through β-catenin stabilization. Cell Death Dis. 2023;14(6):360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang X, Liang Q, Zhang L, Gou H, Li Z, Chen H, Dong Y, Ji J, Yu J. C8orf76 promotes gastric tumorigenicity and metastasis by directly inducing lncRNA DUSP5P1 and associates with patient outcomes. Clin Cancer Res. 2019;25(10):3128–40.

    Article  CAS  PubMed  Google Scholar 

  29. Wang Y, Dong X. High expression of C8orf76 is an independent predictive factor of poor prognosis in patients with breast Cancer. Adv Ther. 2022;39(6):2946–60.

    Article  PubMed  Google Scholar 

  30. Li D, Pan J, Zhang Y, Li Y, Jin S, Zhong C, Chen P, Ma J, Hu W, Fan X et al. C8orf76 modulates ferroptosis in Liver Cancer via Transcriptionally Up-Regulating SLC7A11. Cancers (Basel) 2022, 14(14).

  31. Shi Z, He F, Chen M, Hua L, Wang W, Jiao S, Zhou Z. DNA-binding mechanism of the Hippo pathway transcription factor TEAD4. Oncogene. 2017;36(30):4362–9.

    Article  CAS  PubMed  Google Scholar 

  32. Gao R, Kalathur RKR, Coto-Llerena M, Ercan C, Buechel D, Shuang S, Piscuoglio S, Dill MT, Camargo FD, Christofori G, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med. 2021;13(12):e14351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Qin Y, Pei Z, Feng Z, Lin P, Wang S, Li Y, Huo F, Wang Q, Wang Z, Chen ZN, et al. Oncogenic activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated lipid peroxidation Accumulation. Front Cell Dev Biol. 2021;9:751593.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kim DH, Kim WD, Kim SK, Moon DH, Lee SJ. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis. 2020;11(5):406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang K, Zhang Z, Tsai HI, Liu Y, Gao J, Wang M, Song L, Cao X, Xu Z, Chen H, et al. Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells. Cell Death Differ. 2021;28(4):1222–36.

    Article  CAS  PubMed  Google Scholar 

  36. Shan Y, Yang G, Lu Q, Hu X, Qi D, Zhou Y, Xiao Y, Cao L, Tian F, Pan Q. Centrosomal protein 290 is a novel prognostic indicator that modulates liver cancer cell ferroptosis via the Nrf2 pathway. Aging. 2022;14(5):2367–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Feng H, Liu Y, Gan Y, Li M, Liu R, Liang Z, Liu L, Li L, Chen H, Li G et al. AdipoR1 Regulates Ionizing Radiation-Induced Ferroptosis in HCC cells through Nrf2/xCT Pathway. Oxid Med Cell Longev 2022, 2022:8091464.

  38. Sun J, Zhou C, Zhao Y, Zhang X, Chen W, Zhou Q, Hu B, Gao D, Raatz L, Wang Z, et al. Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation. Redox Biol. 2021;41:101942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bai T, Lei P, Zhou H, Liang R, Zhu R, Wang W, Zhou L, Sun Y. Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells. J Cell Mol Med. 2019;23(11):7349–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hirschhorn T, Stockwell BR. The development of the concept of ferroptosis. Free Radic Biol Med. 2019;133:130–43.

    Article  CAS  PubMed  Google Scholar 

  41. Li J, Liu J, Zhou Z, Wu R, Chen X, Yu C, Stockwell B, Kroemer G, Kang R, Tang D. Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer. Sci Transl Med. 2023;15(720):eadg3049.

    Article  CAS  PubMed  Google Scholar 

  42. Zhou T, Wang T, Zeng K, Qin R, Jin Y, Chen P, Ju G. A nomogram based on a three pyroptosis gene model and clinical parameters for predicting prognosis of hepatocellular carcinoma. Gene. 2022;819:146243.

    Article  CAS  PubMed  Google Scholar 

  43. Xu Q, Zhou L, Yang G, Meng F, Wan Y, Wang L, Zhang L. 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.

    Article  CAS  PubMed  Google Scholar 

  44. Chen Y, Li L, Lan J, Cui Y, Rao X, Zhao J, Xing T, Ju G, Song G, Lou J, et al. CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma. Mol Cancer. 2022;21(1):11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang Q, Bin C, Xue Q, Gao Q, Huang A, Wang K, Tang N. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis. 2021;12(5):426.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Yang F, Li J, Deng H, Wang Y, Lei C, Wang Q, Xiang J, Liang L, Xia J, Pan X, et al. GSTZ1-1 Deficiency activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone. Embo j. 2019;38(15):e101964.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Li J, Wang Q, Yang Y, Lei C, Yang F, Liang L, Chen C, Xia J, Wang K, Tang N. GSTZ1 deficiency promotes hepatocellular carcinoma proliferation via activation of the KEAP1/NRF2 pathway. J Exp Clin Cancer Res. 2019;38(1):438.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Feng Z, Cao K, Sun H, Liu X. SEH1L siliencing induces ferroptosis and suppresses hepatocellular carcinoma progression via ATF3/HMOX1/GPX4 axis. Apoptosis 2024.

  49. Li D, Liu S, Xu J, Chen L, Xu C, Chen F, Xu Z, Zhang Y, Xia S, Shao Y, et al. Ferroptosis-related gene CHAC1 is a valid indicator for the poor prognosis of kidney renal clear cell carcinoma. J Cell Mol Med. 2021;25(7):3610–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang Z, Li M, Liu Y, Qiao Z, Bai T, Yang L, Liu B. Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein responseinduced upregulation of CHAC1 expression. Oncol Rep 2021, 46(5).

  51. Lu M, Lu L, Dong Q, Yu G, Chen J, Qin L, Wang L, Zhu W, Jia H. Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition. Acta Biochim Biophys Sin (Shanghai). 2018;50(4):370–80.

    Article  CAS  PubMed  Google Scholar 

  52. Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W, Sandoval-Gomez G, Clish CB, Doench JG, Schreiber SL. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol. 2020;16(3):302–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cao F, Luo A, Yang C. G6PD inhibits ferroptosis in hepatocellular carcinoma by targeting cytochrome P450 oxidoreductase. Cell Signal. 2021;87:110098.

    Article  CAS  PubMed  Google Scholar 

  54. Li L, Wang X, Xu H, Liu X, Xu K. Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma. Front Mol Biosci. 2022;9:947208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yuan J, Lv T, Yang J, Wu Z, Yan L, Yang J, Shi Y. HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma. Redox Biol. 2022;58:102546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yuan Y, Xu J, Jiang Q, Yang C, Wang N, Liu X, Piao HL, Lu S, Zhang X, Han L, et al. Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis. J Exp Clin Cancer Res. 2024;43(1):133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Suzuki S, Venkatesh D, Kanda H, Nakayama A, Hosokawa H, Lee E, Miki T, Stockwell BR, Yokote K, Tanaka T, et al. GLS2 is a tumor suppressor and a Regulator of ferroptosis in Hepatocellular Carcinoma. Cancer Res. 2022;82(18):3209–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Qi W, Li Z, Xia L, Dai J, Zhang Q, Wu C, Xu S. LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells. Sci Rep. 2019;9(1):16185.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18(1):5–18.

    Article  CAS  PubMed  Google Scholar 

  60. Yan H, Bu P. Non-coding RNA in cancer. Essays Biochem. 2021;65(4):625–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lyu N, Zeng Y, Kong Y, Chen Q, Deng H, Ou S, Bai Y, Tang H, Wang X, Zhao M. Ferroptosis is involved in the progression of hepatocellular carcinoma through the circ0097009/miR-1261/SLC7A11 axis. Ann Transl Med. 2021;9(8):675.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bai T, Liang R, Zhu R, Wang W, Zhou L, Sun Y. MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol. 2020;235(7–8):5637–48.

    Article  CAS  PubMed  Google Scholar 

  63. Zhang B, Bao W, Zhang S, Chen B, Zhou X, Zhao J, Shi Z, Zhang T, Chen Z, Wang L, et al. LncRNA HEPFAL accelerates ferroptosis in hepatocellular carcinoma by regulating SLC7A11 ubiquitination. Cell Death Dis. 2022;13(8):734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhai H, Zhong S, Wu R, Mo Z, Zheng S, Xue J, Meng H, Liu M, Chen X, Zhang G, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Zhang XY, Li SS, Gu YR, Xiao LX, Ma XY, Chen XR, Wang JL, Liao CH, Lin BL, Huang YH, et al. CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis. Mol Cancer. 2024;23(1):113.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in Gene expression regulation. Cell. 2017;169(7):1187–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, et al. M(6)a demethylase ALKBH5 maintains tumorigenicity of Glioblastoma Stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591–e606596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Huang H, Weng H, Chen J. M(6)a modification in Coding and non-coding RNAs: roles and therapeutic implications in Cancer. Cancer Cell. 2020;37(3):270–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fan Z, Yang G, Zhang W, Liu Q, Liu G, Liu P, Xu L, Wang J, Yan Z, Han H, et al. Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11. J Cell Mol Med. 2021;25(21):10197–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. METTL9-SLC7A. 11 axis promotes hepatocellular carcinoma progression through ferroptosis inhibition.

  71. Chen S, Xia H, Sheng L. WTAP-mediated m6A modification on circCMTM3 inhibits hepatocellular carcinoma ferroptosis by recruiting IGF2BP1 to increase PARK7 stability. Dig Liver Dis. 2023;55(7):967–81.

    Article  CAS  PubMed  Google Scholar 

  72. Zada S, Hwang JS, Ahmed M, Lai TH, Pham TM, Elashkar O, Kim DR. Cross talk between autophagy and oncogenic signaling pathways and implications for cancer therapy. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188565.

    Article  CAS  PubMed  Google Scholar 

  73. Bartolini D, Dallaglio K, Torquato P, Piroddi M, Galli F. Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma. Transl Res. 2018;193:54–71.

    Article  PubMed  Google Scholar 

  74. Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020;19(1):12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wu J, Wang Y, Jiang R, Xue R, Yin X, Wu M, Meng Q. Ferroptosis in liver disease: new insights into disease mechanisms. Cell Death Discov. 2021;7(1):276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang Z, Guo M, Li Y, Shen M, Kong D, Shao J, Ding H, Tan S, Chen A, Zhang F, et al. RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2020;16(8):1482–505.

    Article  CAS  PubMed  Google Scholar 

  78. Kang R, Zhu S, Zeh HJ, Klionsky DJ, Tang D. BECN1 is a new driver of ferroptosis. Autophagy. 2018;14(12):2173–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Huang CY, Chen LJ, Chen G, Chao TI, Wang CY. SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma. Int J Mol Sci 2022, 23(19).

  80. Ni X, Hu G, Cai X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit Rev Food Sci Nutr. 2019;59(sup1):S71–80.

    Article  CAS  PubMed  Google Scholar 

  81. Fang S, Hu C, Xu L, Cui J, Tao L, Gong M, Wang Y, He Y, He T, Bi Y. All-trans-retinoic acid inhibits the malignant behaviors of hepatocarcinoma cells by regulating autophagy. Am J Transl Res. 2020;12(10):6793–810.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Sun Y, He Y, Tong J, Liu D, Zhang H, He T, Bi Y. All-trans retinoic acid inhibits the malignant behaviors of hepatocarcinoma cells by regulating ferroptosis. Genes Dis. 2022;9(6):1742–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Li HW, Liu MB, Jiang X, Song T, Feng SX, Wu JY, Deng PF, Wang XY. GALNT14 regulates ferroptosis and apoptosis of ovarian cancer through the EGFR/mTOR pathway. Future Oncol. 2022;18(2):149–61.

    Article  CAS  PubMed  Google Scholar 

  84. Zhang L, Liu W, Liu F, Wang Q, Song M, Yu Q, Tang K, Teng T, Wu D, Wang X et al. IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer. Oxid Med Cell Longev 2020, 2020:1675613.

  85. Sun Y, Berleth N, Wu W, Schlütermann D, Deitersen J, Stuhldreier F, Berning L, Friedrich A, Akgün S, Mendiburo MJ, et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis. 2021;12(11):1028.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Huang SC, Chen YM, Hu YY, Shi YJ, Xiao QW, Li Z, Kang JL, Zhou Q, Shen G, Jia HY. Downregulation of MCF2L Promoted the Ferroptosis of Hepatocellular Carcinoma Cells through PI3K/mTOR Pathway in a RhoA/Rac1 Dependent Manner. Dis Markers 2022, 2022:6138941.

  87. Hu Z, Li L, Li M, Zhang X, Zhang Y, Ran J, Li L. miR-21-5p Inhibits Ferroptosis in Hepatocellular Carcinoma Cells by Regulating the AKT/mTOR Signaling Pathway through MELK. J Immunol Res 2023, 2023:8929525.

  88. Mayoral-Varo V, Jiménez L, Link W. The critical role of TRIB2 in Cancer and Therapy Resistance. Cancers (Basel) 2021, 13(11).

  89. Guo S, Chen Y, Xue X, Yang Y, Wang Y, Qiu S, Cui J, Zhang X, Ma L, Qiao Y, et al. TRIB2 desensitizes ferroptosis via βTrCP-mediated TFRC ubiquitiantion in liver cancer cells. Cell Death Discov. 2021;7(1):196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020;66:89–100.

    Article  CAS  PubMed  Google Scholar 

  91. Santana-Codina N, Gikandi A, Mancias JD. The role of NCOA4-Mediated Ferritinophagy in Ferroptosis. Adv Exp Med Biol. 2021;1301:41–57.

    Article  CAS  PubMed  Google Scholar 

  92. Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, Pikarsky E, Zhu AX, Finn RS. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151–72.

    Article  CAS  PubMed  Google Scholar 

  93. Lai Y, Han X, Xie B, Xu Y, Yang Z, Wang D, Li W, Xie Y, Song W, Zhang X, et al. EZH2 suppresses ferroptosis in hepatocellular carcinoma and reduces sorafenib sensitivity through epigenetic regulation of TFR2. Cancer Sci. 2024;115(7):2220–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li Y, Yang W, Zheng Y, Dai W, Ji J, Wu L, Cheng Z, Zhang J, Li J, Xu X, et al. Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis. J Exp Clin Cancer Res. 2023;42(1):6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hao SH, Ma XD, Xu L, Xie JD, Feng ZH, Chen JW, Chen RX, Wang FW, Tang YH, Xie D, et al. Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma. Drug Resist Updat. 2024;73:101052.

    Article  CAS  PubMed  Google Scholar 

  96. Guo L, Hu C, Yao M, Han G. Mechanism of sorafenib resistance associated with ferroptosis in HCC. Front Pharmacol. 2023;14:1207496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dai T, Vera Y, Salido EC, Yen PH. Characterization of the mouse Dazap1 gene encoding an RNA-binding protein that interacts with infertility factors DAZ and DAZL. BMC Genomics. 2001;2:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang Q, Guo Y, Wang W, Liu B, Yang G, Xu Z, Li J, Liu Z. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res. 2021;399(1):112453.

    Article  CAS  PubMed  Google Scholar 

  99. Huang W, Chen K, Lu Y, Zhang D, Cheng Y, Li L, Huang W, He G, Liao H, Cai L, et al. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. Neoplasia. 2021;23(12):1227–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gao L, Morine Y, Yamada S, Saito Y, Ikemoto T, Tokuda K, Takasu C, Miyazaki K, Shimada M. Nrf2 signaling promotes cancer stemness, migration, and expression of ABC transporter genes in sorafenib-resistant hepatocellular carcinoma cells. PLoS ONE. 2021;16(9):e0256755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sun X, Niu X, Chen R, He W, Chen D, Kang R, Tang D. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology. 2016;64(2):488–500.

    Article  CAS  PubMed  Google Scholar 

  102. Lu Y, Chan YT, Tan HY, Zhang C, Guo W, Xu Y, Sharma R, Chen ZS, Zheng YC, Wang N, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lu Z, Yang H, Shao Y, Sun W, Jiang Y, Li J. IGF2BP3-NRF2 axis regulates ferroptosis in hepatocellular carcinoma. Biochem Biophys Res Commun. 2022;627:103–10.

    Article  CAS  PubMed  Google Scholar 

  104. Zou Y, Sun Z, Sun S. LncRNA HCG18 contributes to the progression of hepatocellular carcinoma via miR-214-3p/CENPM axis. J Biochem. 2020;168(5):535–46.

    Article  CAS  PubMed  Google Scholar 

  105. Li X, Li Y, Lian P, Lv Q, Liu F. 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.

    Article  CAS  PubMed  Google Scholar 

  106. Shi Z, Li Z, Jin B, Ye W, Wang L, Zhang S, Zheng J, Lin Z, Chen B, Liu F, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Liu H, Zhao L, Wang M, Yang K, Jin Z, Zhao C, Shi G. FNDC5 causes resistance to Sorafenib by activating the PI3K/Akt/Nrf2 pathway in Hepatocellular Carcinoma cells. Front Oncol. 2022;12:852095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Murugan AK. mTOR: role in cancer, metastasis and drug resistance. Semin Cancer Biol. 2019;59:92–111.

    Article  CAS  PubMed  Google Scholar 

  109. Li B, Wei S, Yang L, Peng X, Ma Y, Wu B, Fan Q, Yang S, Li X, Jin H, et al. CISD2 promotes resistance to Sorafenib-Induced ferroptosis by regulating Autophagy in Hepatocellular Carcinoma. Front Oncol. 2021;11:657723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Park SJ, Cho SS, Kim KM, Yang JH, Kim JH, Jeong EH, Yang JW, Han CY, Ku SK, Cho IJ, et al. Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicol Appl Pharmacol. 2019;379:114665.

    Article  CAS  PubMed  Google Scholar 

  111. Liu Z, Ma C, Wang Q, Yang H, Lu Z, Bi T, Xu Z, Li T, Zhang L, Zhang Y, et al. Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma. Biochem Biophys Res Commun. 2022;589:247–53.

    Article  CAS  PubMed  Google Scholar 

  112. Gunassekaran GR, Poongkavithai Vadevoo SM, Baek MC, Lee B. M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages. Biomaterials. 2021;278:121137.

    Article  CAS  PubMed  Google Scholar 

  113. Hao X, Zheng Z, Liu H, Zhang Y, Kang J, Kong X, Rong D, Sun G, Sun G, Liu L, et al. Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti-PD1 immunotherapy in hepatocellular carcinoma based on single-cell RNA sequencing. Redox Biol. 2022;56:102463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tang B, Zhu J, Wang Y, Chen W, Fang S, Mao W, Xu Z, Yang Y, Weng Q, Zhao Z, et al. Targeted xCT-mediated ferroptosis and Protumoral polarization of Macrophages is effective against HCC and enhances the efficacy of the Anti-PD-1/L1 response. Adv Sci (Weinh). 2023;10(2):e2203973.

    Article  PubMed  Google Scholar 

  115. Huang J, Pan H, Sun J, Wu J, Xuan Q, Wang J, Ke S, Lu S, Li Z, Feng Z, et al. TMEM147 aggravates the progression of HCC by modulating cholesterol homeostasis, suppressing ferroptosis, and promoting the M2 polarization of tumor-associated macrophages. J Exp Clin Cancer Res. 2023;42(1):286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang D, Man D, Lu J, Jiang Y, Ding B, Su R, Tong R, Chen J, Yang B, Zheng S, et al. Mitochondrial TSPO promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion. Adv Sci (Weinh). 2023;10(15):e2206669.

    Article  PubMed  Google Scholar 

  117. Cheu JW, Lee D, Li Q, Goh CC, Bao MH, Yuen VW, Zhang MS, Yang C, Chan CY, Tse AP, et al. Ferroptosis Suppressor Protein 1 inhibition promotes Tumor Ferroptosis and Anti-tumor Immune responses in Liver Cancer. Cell Mol Gastroenterol Hepatol. 2023;16(1):133–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Li Y, Hu G, Huang F, Chen M, Chen Y, Xu Y, Tong G. MAT1A suppression by the CTBP1/HDAC1/HDAC2 Transcriptional Complex Induces Immune Escape and reduces ferroptosis in Hepatocellular Carcinoma. Lab Invest. 2023;103(8):100180.

    Article  PubMed  Google Scholar 

  119. Conche C, Finkelmeier F, Pešić M, Nicolas AM, Böttger TW, Kennel KB, Denk D, Ceteci F, Mohs K, Engel E, et al. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut. 2023;72(9):1774–82.

    Article  CAS  PubMed  Google Scholar 

  120. Zheng Y, Wang Y, Lu Z, Wan J, Jiang L, Song D, Wei C, Gao C, Shi G, Zhou J, et al. PGAM1 inhibition promotes HCC Ferroptosis and synergizes with Anti-PD-1 Immunotherapy. Adv Sci (Weinh). 2023;10(29):e2301928.

    Article  PubMed  Google Scholar 

  121. Wang S, Zhu L, Li T, Lin X, Zheng Y, Xu D, Guo Y, Zhang Z, Fu Y, Wang H, et al. Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma. Cell Rep Med. 2024;5(2):101415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021;12(8):599–620.

    Article  CAS  PubMed  Google Scholar 

  123. Shang Y, Luo M, Yao F, Wang S, Yuan Z, Yang Y. Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells. Cell Signal. 2020;72:109633.

    Article  CAS  PubMed  Google Scholar 

  124. Yang M, Wu X, Hu J, Wang Y, Wang Y, Zhang L, Huang W, Wang X, Li N, Liao L, et al. COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma. J Hepatol. 2022;76(5):1138–50.

    Article  CAS  PubMed  Google Scholar 

  125. Zhang T, Sun L, Hao Y, Suo C, Shen S, Wei H, Ma W, Zhang P, Wang T, Gu X, et al. ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1. Nat Cancer. 2022;3(1):75–89.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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Funding

This work was supported by the National Nature Science Foundation of China (No. 81902500 & 82460489), the China Postdoctoral Science Foundation (2022MD723764), the Guangxi Natural Science Foundation (No. 2024GXNSFAA010065 & 2023GXNSFBA026108) and the Innovation Project of Guangxi Graduate Education (YCSW2024271).

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Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China

    Chuanjie Liao, Youwu He, Xinning Luo & Ganlu Deng

  2. Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, China

    Chuanjie Liao, Youwu He, Xinning Luo & Ganlu Deng

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  1. Chuanjie Liao
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  2. Youwu He
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  3. Xinning Luo
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  4. Ganlu Deng
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CL designed this study, GD directed the study, YH and XL sorted out documents and made tables. CL drafted the manuscript and drew figures. All authors reviewed the manuscript.

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Correspondence to Ganlu Deng.

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Liao, C., He, Y., Luo, X. et al. Ferroptosis: insight into the treatment of hepatocellular carcinoma. Cancer Cell Int 24, 376 (2024). https://doi.org/10.1186/s12935-024-03559-z

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Keywords

Cancer Cell International

ISSN: 1475-2867

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