Ferroptosis Mechanisms in Liver Pathologies

Ferroptosis is an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides and failure of antioxidant systems. In the healthy liver, tight control of iron uptake, storage and export maintains redox balance. In pathological settings, dysregulated iron homeostasis and enhanced generation of polyunsaturated fatty-acid peroxides overwhelm protective enzymes, notably glutathione peroxidase 4, leading to membrane damage and cell demise. This process contributes to diverse liver conditions – from acute drug-induced injury and non-alcoholic steatohepatitis through fibrotic remodelling to cirrhosis and hepatocellular carcinoma. Key modulators include the cystine/glutamate antiporter system Xc–, the lipid-repair enzyme GPX4, transcription factors such as NRF2 and p53, and secreted iron-binding proteins. Therapeutic strategies aim to restore antioxidant defences, chelate excess iron or selectively induce ferroptosis in malignant hepatocytes.

Research from Nature Portfolio

Recent studies have revealed that reprogramming of lipid metabolism determines sensitivity to ferroptosis in liver cancers. One investigation demonstrated that overexpression of an unconventional prefoldin interactor suppresses p53 and enhances stearoyl-CoA desaturase-1, conferring resistance to tyrosine kinase inhibitor-induced ferroptosis, while combined inhibition of desaturase activity restores cell death. Another report identified a cytokine-driven network in which loss of a liver tumour suppressor activates NF-κB signalling and upregulates an iron-sequestering protein, depleting labile iron pools and blocking ferroptosis in hepatocellular carcinoma. Neutralisation of the iron-binding cytokine reinstated ferroptotic vulnerability and enhanced sorafenib efficacy in patient-derived models. Together, these findings highlight interconnected roles for lipid enzymes, p53 modulation and iron-sequestering factors in orchestrating ferroptosis resistance in liver malignancies.

Ferroptosis Mechanisms in Liver Pathologies publication trend

The graph below shows the total number of articles in ferroptosis mechanisms in liver pathologies across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: Iron-dependent cell death caused by lipid peroxide accumulation.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids in membranes.

Glutathione peroxidase 4 (GPX4): Enzyme that reduces lipid hydroperoxides and prevents ferroptosis.

System Xc–: Cystine/glutamate antiporter essential for glutathione synthesis and redox balance.

Nuclear factor erythroid 2-related factor 2 (NRF2): Transcription factor regulating antioxidant gene expression.

Stearoyl-CoA desaturase-1 (SCD1): Enzyme converting saturated fatty acids to monounsaturated fatty acids, affecting membrane susceptibility to peroxidation.

References

1. The multifaceted role of ferroptosis in liver disease. Cell Death & Differentiation (2022).
2. URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers. Nature Communications (2023).
3. A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nature Communications (2021).
4. Protein phosphatase 2A-B55β mediated mitochondrial p-GPX4 dephosphorylation promoted sorafenib-induced ferroptosis in hepatocellular carcinoma via regulating p53 retrograde signaling. Theranostics (2023).
5. Ferroptosis in Liver Diseases: An Overview. International Journal of Molecular Sciences (2020).
6. Ferroptosis in liver disease: new insights into disease mechanisms. Cell Death Discovery (2021).