Molecular Targets of Ferroptosis in Hepatocellular Carcinoma

Liao, Hao; Shi, Juan; Wen, Ke; Lin, Jianhong; Liu, Qinghua; Shi, Bingchao; Yan, Yongcong; Xiao, Zhiyu

doi:10.2147/jhc.s325593

Cited by 20 publications

(17 citation statements)

References 117 publications

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“…Although such preclinical data suggest a promising anticancer approach via the induction of ferroptosis, clinical studies are currently not available and the usage of ferroptosis inducing substances need to be further studied in situ [ 43 , 48 ]. Preclinical data regarding hepatocellular carcinoma demonstrate a promising outlook to combat liver cancer with the induction of ferroptosis [ 49 , 50 ]. The following chapter discusses the conceptual background why ferroptosis might be especially attractive for novel approaches in HCC treatment.…”

Section: The Potential Of Ferroptosis In (Hepatocellular) Cancer Therapymentioning

confidence: 99%

“…In HCC, ferroptosis might play a different role compared to other forms of liver diseases. Several studies demonstrated that iron overload in HCC is a driver of tumorigenesis, proliferation and tumor growth [ 49 , 67 ]. Therefore, one approach of anticancer therapy might be the maintenance or increase of abnormal iron levels in HCC cells in order to induce overproduction of ROS resulting in ferroptotic cell death.…”

Section: The Potential Of Ferroptosis In (Hepatocellular) Cancer Therapymentioning

confidence: 99%

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Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

Bekric

Ocker

Mayr

et al. 2022

Cancers

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Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC.

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Section: The Potential Of Ferroptosis In (Hepatocellular) Cancer Therapymentioning

confidence: 99%

Section: The Potential Of Ferroptosis In (Hepatocellular) Cancer Therapymentioning

confidence: 99%

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

Bekric

Ocker

Mayr

et al. 2022

Cancers

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“…It may not involve a direct kinase inhibition and/or binding to an alternative target such as an unknown kinase whose activity is necessary for system x c − [161]. Besides inhibiting tumor proliferation through the RAF/MEK/ERK signaling pathway, sorafenib can block tumor angiogenesis via VEGFR and platelet-derived growth factor receptor (PDGFR) [162]. Sorafenib-induced ferroptotic anticancer activity can be enhanced by blocking another critical regulator named metallothionein (MT)-1G that also plays an antioxidant role [163].…”

Section: Fin56mentioning

confidence: 99%

“…NRF2 is involved in iron and ROS metabolism, where it protects HCC cells against ferroptosis through upregulation of multiple genes such as HMOX1 [122]. The common leucine zipper transcription factor NRF2 is essential for redox homeostasis and regulates the metabolism of multiple cancer cells, which makes it a promising target for tumor therapy [162]. Several studies have assessed the role of NRF2 in ferroptosis, and upregulation of iron and ROS by genetic or pharmacological inhibition of NRF2 expression leads to an enhanced anti-tumor effect of erastin and sorafenib [153].…”

Section: Targeting Nrfmentioning

confidence: 99%

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

Kusnick

Bruneau

Tacke

et al. 2022

Immuno

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Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.

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“…On the other hand, immunogenic deaths, ferroptosis, and pyroptosis can result in immune responses due to the release of various intracellular contents, most acting as pro-inflammatory signals. Though the role of ferroptosis and pyroptosis in HCC prognosis had been previously discussed ( 6 , 7 ), how non-immunogenic apoptosis as well as immunogenic ferroptosis and pyroptosis cross-talk at the gene and protein levels and collaboratively contribute to the development of the immunosuppressive HCC TME remain to be further addressed.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance

Chen

Hong

et al. 2022

Front. Immunol.

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Hepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. However, how apoptosis, ferroptosis, and pyroptosis are involved in constructions of the immunosuppressive TME and their underlying cross-talk remains to be further unveiled. In this work, we deciphered the immunosuppressive landscape of HCC TME, which demonstrated high expressions of inhibitory checkpoint molecules and infiltration of protumor immune cells but low infiltration of antitumor effector immune cells. Further investigations unequivocally revealed that marker genes of apoptosis, ferroptosis, and pyroptosis are closely correlated with expressions and infiltrations of inhibitory checkpoint molecules and immune cells and that higher “-optosis” links to poorer patient prognosis. Notably, such three types of “-optosis” interact with each other at both the gene and protein levels, suggesting that they conspiringly induce the establishment of the immunosuppressive HCC TME. Interestingly, examinations of circulating γδ T cells in HCC patients revealed a noticeable dysfunction phenotype. The strikingly elevated ratio of the Vδ1+ versus the Vδ2+ subset suggested that the Vδ1+/Vδ2+ ratio would be a potential biomarker for the diagnosis and prognosis in HCC patients. Altogether, this work thoroughly decrypted the underlying correlations between apoptosis, ferroptosis, and pyroptosis and the formation of immunosuppressive HCC TME and, meanwhile, indicated that allogeneic Vδ2+ γδ T-cell transfer would be a promising adjuvant strategy for renormalizing circulating γδ T cell and thus achieving sound clinical efficacy against HCC.

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Molecular Targets of Ferroptosis in Hepatocellular Carcinoma

Cited by 20 publications

References 117 publications

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance

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