☆ 4.6 Review

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

CANCERS (2022)

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Review Biochemistry & Molecular Biology

Iron and liver cancer: an inseparable connection

Keisuke Hino et al.

Summary: Iron is essential for organisms, playing critical roles in cellular functions. However, excess iron can cause damage to cells and cellular DNA. Most excess iron is stored in the liver, and liver diseases such as haemochromatosis are associated with a higher risk of liver cancer. Studies have shown that iron plays important roles in the development of liver cancer.

FEBS JOURNAL (2022)

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Article Chemistry, Physical

A cascaded copper-based nanocatalyst by modulating glutathione and cyclooxygenase-2 for hepatocellular carcinoma therapy

Hailong Tian et al.

Summary: A novel cascaded copper-based metal-organic framework therapeutic nanocatalyst was reported for amplified hepatocellular carcinoma therapy by integrating a COX-2 inhibitor and a chemotherapeutic agent to trigger ferroptosis-mediated therapy.

JOURNAL OF COLLOID AND INTERFACE SCIENCE (2022)

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Article Gastroenterology & Hepatology

Iron Chaperone Poly rC Binding Protein 1 Protects Mouse Liver From Lipid Peroxidation and Steatosis

Olga Protchenko et al.

Summary: PCBP1 is an iron chaperone protein critical for managing iron homeostasis in hepatocytes, without which can lead to iron accumulation, cell death, and liver disease. Dietary iron restriction and antioxidant therapy can prevent liver disease caused by PCBP1 deficiency.

HEPATOLOGY (2021)

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Article Chemistry, Multidisciplinary

ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma

Ji Feng et al.

Summary: ACSL4 plays a crucial role in sorafenib treatment and its high expression may predict sensitivity of HCC patients to sorafenib. The findings of this study could have important translational impacts in the precise treatment of HCC patients.

ACTA PHARMACOLOGICA SINICA (2021)

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Article Chemistry, Multidisciplinary

Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma

Zhong-jie Li et al.

Summary: The combination therapy of artesunate and sorafenib has been shown to synergistically induce ferroptosis in HCC cells, enhancing anticancer effects. The mechanism involves artesunate-induced lysosome activation synergizing with sorafenib-mediated oxidative stress, leading to lipid peroxidation and ferroptosis.

ACTA PHARMACOLOGICA SINICA (2021)

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Article Cell Biology

A scoring model based on ferroptosis genes for prognosis and immunotherapy response prediction and tumor microenvironment evaluation in liver hepatocellular carcinoma

Lei Gao et al.

Aging-US (2021)

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Article Biochemistry & Molecular Biology

Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis

Yanchun Li et al.

Summary: The study reveals that sorafenib inhibits the viability, proliferation, and migration of HCC cells by inducing ferroptosis, which can be reversed by glutathione supplementation to reduce mitochondrial reactive oxygen species and lipid peroxides accumulation, enhancing HCC cells' vulnerability to sorafenib.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2021)

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Article Biochemistry & Molecular Biology

Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease

Wen-Dai Bao et al.

Summary: Iron homeostasis disturbance and ferroptosis play critical roles in the pathogenesis and progression of Alzheimer's disease, and targeting these processes may provide promising therapeutic approaches for this disease.

CELL DEATH AND DIFFERENTIATION (2021)

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Article Pharmacology & Pharmacy

Ferroptosis as a new therapeutic opportunity for nonviral liver disease

Min Jia et al.

Summary: Ferroptosis plays a crucial role in various nonviral liver diseases, making it an ideal target for their treatment. This review discusses the latest findings on ferroptosis and potential therapeutic drugs targeting it for nonviral liver diseases, providing further directions in the field.

EUROPEAN JOURNAL OF PHARMACOLOGY (2021)

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Review Cell Biology

Ferroptosis: mechanisms, biology and role in disease

Xuejun Jiang et al.

Summary: Ferroptosis, as a form of regulated cell death driven by iron-dependent phospholipid peroxidation, has seen significant growth in research in recent years. Studies have focused on molecular mechanisms, regulation, and functions of ferroptosis, linking this cell death modality to various pathologies and proposing its roles in normal physiology and potential therapeutic targeting.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2021)

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Article Cell Biology

A Marine Terpenoid, Heteronemin, Induces Both the Apoptosis and Ferroptosis of Hepatocellular Carcinoma Cells and Involves the ROS and MAPK Pathways

Wen-Tsan Chang et al.

Summary: Heteronemin, a marine natural product, has shown inhibitory effects on hepatocellular carcinoma cells by inducing apoptosis through modulation of ROS, MAPK signaling pathways, and other mechanisms. These findings suggest that with structural modification, heteronemin could potentially serve as a potent therapeutic agent against HCC.

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY (2021)

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Review Cell Biology

Characteristics and Biomarkers of Ferroptosis

Xin Chen et al.

Summary: The induction and consequences of regulated cell death (RCD) result in changes in gene and protein expression, biochemical pathways, cell morphology, and size. Among different forms of RCD, ferroptosis, driven by iron overload and lipid peroxidation, is implicated in various pathological conditions and diseases. The ferroptotic response can be fine-tuned through oxidative stress and antioxidant pathways, and a series of inducers or inhibitors have been developed targeting metabolism-related proteins.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Article Oncology

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung et al.

Summary: The global cancer burden in 2020 saw an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths. Female breast cancer surpassed lung cancer as the most commonly diagnosed cancer, while lung cancer remained the leading cause of cancer death. These trends are expected to rise in 2040, with transitioning countries experiencing a larger increase compared to transitioned countries due to demographic changes and risk factors associated with globalization and a growing economy. Efforts to improve cancer prevention measures and provision of cancer care in transitioning countries will be crucial for global cancer control.

CA-A CANCER JOURNAL FOR CLINICIANS (2021)

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Review Oncology

Broadening horizons: the role of ferroptosis in cancer

Xin Chen et al.

Summary: Ferroptosis is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, and can be induced by various agents to suppress tumor growth while also potentially triggering inflammation-associated immunosuppression. The extent of ferroptosis's impact on tumor biology and its interactions with other signaling pathways are still under investigation.

NATURE REVIEWS CLINICAL ONCOLOGY (2021)

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Article Multidisciplinary Sciences

NUPR1 is a critical repressor of ferroptosis

Jiao Liu et al.

Summary: Ferroptosis is a type of iron-dependent regulated cell death, and the stress-inducible transcription factor NUPR1 may drive resistance to ferroptosis by mediating LCN2 expression. Blocking the NUPR1-LCN2 pathway can increase ferroptosis inducer activity and worsen conditions like pancreatitis in relevant mouse models.

NATURE COMMUNICATIONS (2021)

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Article Biochemistry & Molecular Biology

Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation

Jialei Sun et al.

Summary: QSOX1 acts as a cellular prooxidant in HCC, sensitizing cells to oxidative stress by inhibiting NRF2. There is a negative correlation between QSOX1 and NRF2 expression in tumor tissues from HCC patients, and QSOX1 can enhance sorafenib-induced ferroptosis.

REDOX BIOLOGY (2021)

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Article Oncology

The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma

Zaoqu Liu et al.

Summary: Two heterogeneous ferroptosis subtypes with distinct metabolic and immune characteristics were identified in hepatocellular carcinoma. These subtypes showed differential sensitivity to immunotherapy and sorafenib. Additionally, a reliable risk signature for prognosis and immunotherapy assessment was developed.

FRONTIERS IN ONCOLOGY (2021)

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Review Biology

Lipid Metabolism and Ferroptosis

Ji-Yoon Lee et al.

Summary: Ferroptosis is a type of iron-dependent regulated necrosis induced by lipid peroxidation in cellular membranes. Polyunsaturated fatty acids associated with specific phospholipids are responsible for ferroptosis-inducing lipid peroxidation. Cells take up essential fatty acids from blood to produce PUFAs, which undergo lipid peroxidation through various pathways tightly regulated by metabolic and signaling pathways.

BIOLOGY-BASEL (2021)

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Article Biotechnology & Applied Microbiology

Self-amplification of oxidative stress with tumour microenvironment-activatable iron-doped nanoplatform for targeting hepatocellular carcinoma synergistic cascade therapy and diagnosis

Qiao-Mei Zhou et al.

Summary: The study presents a rationally designed nanoplatform that induces tumor cell death through complementary ferroptosis and apoptosis, and can guide and monitor treatment under magnetic resonance imaging.

JOURNAL OF NANOBIOTECHNOLOGY (2021)

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Article Genetics & Heredity

Identification of a Ferroptosis-Related Long Noncoding RNA Prognostic Signature and Its Predictive Ability to Immunotherapy in Hepatocellular Carcinoma

Liang Wang et al.

Summary: The study identified a ferroptosis-related lncRNA signature that accurately predicts the overall survival of HCC patients and may serve as an independent clinical factor for patients' outcomes. These lncRNAs may remodel the tumor microenvironment (TME) and affect the anti-cancer ability of ICBs, potentially acting as an indicator for the response to immunotherapy in HCC.

FRONTIERS IN GENETICS (2021)

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Article Oncology

A Novel Ferroptosis-Related 4-Gene Prognostic Signature for Cholangiocarcinoma and Photodynamic Therapy

Zi-jian Zhang et al.

Summary: Cholangiocarcinoma is the second most common malignant tumor in the hepatobiliary system, but there is a lack of public data and prognostic studies compared to hepatocellular carcinoma. Ferroptosis has been identified as an important area of tumor research, with potential implications for hepatobiliary cancers. This study constructed a ferroptosis gene signature model using LASSO-penalized Cox regression analysis and identified PDT-sensitive genes that could enhance the efficacy of PDT for cholangiocarcinoma.

FRONTIERS IN ONCOLOGY (2021)

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Review Oncology

Stress Granules in the Anti-Cancer Medications Mechanism of Action: A Systematic Scoping Review

Mohammad Reza Asadi et al.

Summary: Stress granules play a critical role in minimizing stress-related damage and have emerged as important mediators in human health, particularly in cancer formation, development, and drug response. Recent studies have shown that SG components influence the responses of anti-cancer medications through tumor-associated signaling pathways. SG proteins are known for their involvement in translation, control of mRNA stability, and dual functionality in the cytoplasm and nucleus.

FRONTIERS IN ONCOLOGY (2021)

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Review Oncology

The Role of Iron in Cancer Progression

Qianqian Guo et al.

Summary: Iron is closely related to the occurrence and development of tumors, playing a crucial role in cell death. Research on iron metabolism disorders and the use of iron in tumor treatment is important for the prevention and treatment of tumors.

FRONTIERS IN ONCOLOGY (2021)

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Review Cell Biology

The Emerging Role of Ferroptosis in Liver Diseases

Si Chen et al.

Summary: Ferroptosis, mediated by iron-dependent lipid peroxide, participates in various diseases with distinct roles. Regulating ferroptosis may have dual effects in counteracting the progression of liver diseases and the development of drug resistance.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Article Chemistry, Medicinal

Small-Molecule Inhibitors of Reactive Oxygen Species Production

Elisa Sassetti et al.

Summary: Reactive oxygen species (ROS) play vital roles in physiological cellular processes, and maintaining appropriate levels of cellular ROS is important for redox homeostasis. Directly targeting the sources of ROS production has become a key focus in research due to the potential link between high ROS concentrations and severe diseases.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

Computational Identification of Immune- and Ferroptosis-Related LncRNA Signature for Prognosis of Hepatocellular Carcinoma

Anmin Huang et al.

Summary: Long non-coding RNAs (lncRNAs) play important roles in various pathophysiological processes, including cancer, with frequent dysregulation in hepatocellular carcinoma (HCC). By combining ferroptosis, immunity, and lncRNA, potential biomarkers for clinical cancer therapy have been identified. The development of an immune- and ferroptosis-related lncRNA risk signature (IFLSig) using bioinformatics methods has shown association with prognosis in HCC patients.

FRONTIERS IN MOLECULAR BIOSCIENCES (2021)

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Article Cell Biology

NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner

Can Huang et al.

Summary: Experimental results demonstrate that ZZW-115-induced ferroptosis mediated by NUPR1 inhibitor can be rescued by Fer-1 and TFAM supplementation, triggering ferroptotic activity in cells derived from PDAC and HCC. Additionally, ZZW-115 treatment leads to alterations in mitochondrial morphology and function, which can be rescued by Fer-1 and NAC.

CELL DEATH DISCOVERY (2021)

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Review Cell Biology

Ferroptosis in liver disease: new insights into disease mechanisms

Jing Wu et al.

Summary: This review outlines the characteristics of ferroptosis, its relevance in liver diseases, and the molecular mechanisms underlying common liver diseases. Challenges and promises for future investigations in ferroptosis regulation as a potential therapeutic target in clinical practice are also highlighted.

CELL DEATH DISCOVERY (2021)

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Article Cell Biology

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

Qiujie Wang et al.

Summary: The study revealed that GSTZ1 enhances sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells, and the combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment.

CELL DEATH & DISEASE (2021)

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Review Oncology

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

Matthias Ocker et al.

Summary: This paper summarizes the current status of immunotherapy options for hepatocellular carcinoma (HCC), emphasizing the importance of combination with locoregional therapies to improve patient outcomes. It briefly discusses novel pathways and targets for immunologic drug development to increase response rates in HCC.

CANCERS (2021)

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Article Oncology

Ferroptosis is involved in the progression of hepatocellular carcinoma through the circ0097009/miR-1261/SLC7A11 axis

Ning Lyu et al.

Summary: In this study, circRNA circ0097009 was found to be significantly upregulated in HCC tissues and cell lines, and it acted as a competing endogenous RNA to regulate the expression of SLC7A11 by sponging miR-1261 in HCC. Circ0097009 may serve as a diagnostic biomarker for HCC and a potential therapeutic target for HCC treatment.

ANNALS OF TRANSLATIONAL MEDICINE (2021)

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Review Biochemistry & Molecular Biology

Organelle-specific regulation of ferroptosis

Xin Chen et al.

Summary: Ferroptosis, characterized by iron-dependent lipid peroxidation, is involved in various pathological conditions. The cellular machinery responsible for ferroptosis integrates signals from organelles to determine the engagement in the lethal process.

CELL DEATH AND DIFFERENTIATION (2021)

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Article Biochemistry & Molecular Biology

H-ferritin suppression and pronounced mitochondrial respiration make Hepatocellular Carcinoma cells sensitive to RSL3-induced ferroptosis

Michela Asperti et al.

Summary: The study showed that highly differentiated HepG2 cells are more sensitive to RSL3-induced ferroptosis, while the downregulation of H-ferritin makes HA22T/VGH more susceptible to ferroptosis. Only H-ferritin appears to be involved in protecting cells from this death process.

FREE RADICAL BIOLOGY AND MEDICINE (2021)

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Review Biochemistry & Molecular Biology

The Emerging Role of Stress Granules in Hepatocellular Carcinoma

Dobrochna Dolicka et al.

Summary: Stress granules play a crucial role in protecting and silencing mRNA during cellular adaptation to harmful conditions, impacting the onset and development of various diseases. In the liver, abnormal expression of SG components and formation of SGs are associated with chronic liver diseases, hepatocellular carcinoma, and resistance to anti-cancer drugs.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Cell Biology

A novel ferroptosis phenotype-related clinical-molecular prognostic signature for hepatocellular carcinoma

Tuo Deng et al.

Summary: In this study, transcriptome and methylome data from 374 HCC cases were analyzed to identify two distinct ferroptosis phenotypes (Ferroptosis-H and Ferroptosis-L), and a 15-gene ferroptosis-related prognostic model (FPM) was developed. These findings may be useful for clinical decision-making in stratifying patients with HCC.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021)

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Article Cell Biology

Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines

Jiashuo Zheng et al.

Summary: Sorafenib does not induce ferroptosis and only a subset of tumor cell lines experience ferroptosis in response to system x(c)(-) inhibitors. These findings suggest that different tumor cells exhibit varying responses to ferroptosis.

CELL DEATH & DISEASE (2021)

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Article Oncology

Identification of a Ferroptosis-Related Signature Model Including mRNAs and lncRNAs for Predicting Prognosis and Immune Activity in Hepatocellular Carcinoma

Zi-An Chen et al.

Summary: A novel ferroptosis-related mRNA/lncRNA signature model was constructed for prognostic prediction and immune evaluation in HCC patients, showing good performance with AUC of 0.830 and 0.806 in the training and test groups. The risk score was identified as an independent prognostic factor via multivariate Cox regression analysis.

FRONTIERS IN ONCOLOGY (2021)

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Review Oncology

Molecular Targets of Ferroptosis in Hepatocellular Carcinoma

Hao Liao et al.

Summary: Ferroptosis is a unique form of regulated cell death caused by intracellular iron accumulation and lipid peroxidation. Research progress on ferroptosis in hepatocellular carcinoma may lead to the development of novel therapeutic targets and markers to improve patient prognosis.

JOURNAL OF HEPATOCELLULAR CARCINOMA (2021)

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Article Medicine, Research & Experimental

Designer exosomes for targeted and efficient ferroptosis induction in cancer via chemo-photodynamic therapy

Jianbing Du et al.

Summary: This study successfully designed an exosome-based platform to deliver ferroptosis inducer and photosensitizer into liver cancer cells, inducing cell death significantly while minimizing toxicity to the liver and kidney.

THERANOSTICS (2021)

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Suman Mukhopadhyay et al.

Summary: This review highlights the metabolic reprogramming mediated by oncogenic RAS in cancer and explores the potential novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers. Mukhopadhyay, Vander Heiden, and McCormick provide insights into the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming, and opportunities for therapeutic targeting of these cancers.

NATURE CANCER (2021)

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Article Medicine, Research & Experimental

Manganese porphyrin-based metal-organic framework for synergistic sonodynamic therapy and ferroptosis in hypoxic tumors

Qingbo Xu et al.

Summary: The manganese porphyrin-based metal-organic framework (Mn-MOF) demonstrates great potential in enhancing cancer therapy through sonodynamic therapy and ferroptosis, showing strong anticancer activity and antitumor immunity in hypoxic tumors.

THERANOSTICS (2021)

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Review Biochemistry & Molecular Biology

Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis-A Novel Form of Non-Apoptotic Cell Death?

Ricardo U. Macias-Rodriguez et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)

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Ionizing radiation induces ferroptosis in granulocyte-macrophage hematopoietic progenitor cells of murine bone marrow

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MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells

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Time Course of Changes in Sorafenib-Treated Hepatocellular Carcinoma Cells Suggests Involvement of Phospho-Regulated Signaling in Ferroptosis Induction

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JOURNAL OF HEPATOLOGY (2020)

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Ferroptosis in Liver Diseases: An Overview

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Saponin Formosanin C-Induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells

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Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5

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Solasonine promotes ferroptosis of hepatoma carcinoma cells via glutathione peroxidase 4-induced destruction of the glutathione redox system

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Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma

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Four Autophagy-Related lncRNAs Predict the Prognosis of HCC through Coexpression and ceRNA Mechanism

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Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration

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HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications

Youbo Zhao et al.

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Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

Yang Liu et al.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2020)

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Alberto Piperno et al.

TRANSLATIONAL GASTROENTEROLOGY AND HEPATOLOGY (2020)

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Article Biochemistry & Molecular Biology

DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin

Jing Du et al.

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Ferroptosis, a new form of cell death: opportunities and challenges in cancer

Yanhua Mou et al.

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GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone

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Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells

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Ferritin heavy chain protects the developing wing from reactive oxygen species and ferroptosis

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NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis

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A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53

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FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

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