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Cellular and Molecular Biology

Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy

British Journal of Cancer volume 128, pages 190–205 (2023)Cite this article

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Abstract

Hepatocellular carcinoma is the most prevalent form of primary liver cancer with a multifactorial aetiology comprising genetic, environmental, and behavioural factors. Evading cell death is a defining hallmark of hepatocellular carcinoma, underpinning tumour growth, progression, and therapy resistance. Ferroptosis is a form of nonapoptotic cell death driven by an array of cellular events, including intracellular iron overload, free radical production, lipid peroxidation and activation of various cell death effectors, ultimately leading to rupture of the plasma membrane. Although induction of ferroptosis is an emerging strategy to suppress hepatocellular carcinoma, malignant cells manage to develop adaptive mechanisms, conferring resistance to ferroptosis and ferroptosis-inducing drugs. Herein, we aim at elucidating molecular mechanisms and signalling pathways involved in ferroptosis and offer our opinions on druggable targets and new therapeutic strategy in an attempt to restrain the growth and progression of hepatocellular carcinoma through induction of ferroptotic cell death.

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Fig. 1: Iron metabolism, overload and ferroptosis.
Fig. 2: Ferroptosis mechanisms and regulations.
Fig. 3: Signalling pathways and regulation of ferroptosis.
Fig. 4: Autophagy and ferroptosis.
Fig. 5: NRF2-keap1 pathway dictates degradation or nuclear translocation of NRF2.
Fig. 6: Potential compounds targeting NRF2 at different stages of HCC progression.

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Acknowledgements

The authors wish to express our sincere apology to those authors whose important work cannot be discussed and cited due to page limitations. GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR)—Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalised Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001.

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Authors and Affiliations

  1. Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, China

    Amir Ajoolabady & Jun Ren

  2. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Daolin Tang

  3. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France

    Guido Kroemer

  4. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

    Guido Kroemer

  5. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

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  1. Amir Ajoolabady
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  4. Jun Ren
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AA has written the initial draft of the manuscript, and DT, GK and JR have contributed to the revising, editing and finalising of the manuscript.

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Correspondence to Daolin Tang, Guido Kroemer or Jun Ren.

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Competing interests

GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sanofi, Sotio, Tollys, Vascage and Vasculox/Tioma. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. The remaining authors declare no competing interests.

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Glossary

Autophagy

An evolutionarily conserved process in eukaryote cells mediating engulfment of damaged organelles or cellular components within transitory organelles, so-called, autophagosomes, which subsequently fuse with lysosomes for ultimate degradation of the engulfed cargo.

Cathepsin B/L

Cathepsin B/L are lysosomal cysteine proteases playing a role in cellular functions, including intracellular proteolysis.

Chronic hepatitis

Refers to liver inflammation and impairment inflicted by hepatitis B and C viruses and drug toxicity.

Ferrireductases

A group of enzymes that mediate the reduction of Fe3+ to Fe2+.

Hemochromatosis

A disorder caused by accumulation and build-up of extra iron in the body.

Methylome

A technique analysing the distribution of 5-methylcytosine in the entire genome.

Myristoylation

A lipid modification mechanism in which a fatty acid known as myristic acid binds to the N-terminal domain of a protein.

Non-alcoholic steatohepatitis (NASH)

Refers to liver inflammation and impairment induced by fat accumulation in the liver.

Saponin

Natural glycosides, which constitute sugars like apiose, arabinose, galactose, and glucose, are found abundantly in plants.

Transcriptome

Refers to a thorough range/record of expressed mRNAs within an organism.

Xenobiotics

Refers to chemical compounds that are naturally produced or exists within an organism.

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Ajoolabady, A., Tang, D., Kroemer, G. et al. Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy. Br J Cancer 128, 190–205 (2023). https://doi.org/10.1038/s41416-022-01998-x

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