Ferroptosis–Immune Crosstalk Between MASH and HCC: Gut | September 2026
Introduction:
Progression from MASH to fibrosis and hepatocellular carcinoma (HCC) involves lipotoxicity, oxidative stress, inflammation, and hepatocyte death. This review positions ferroptosis—iron-dependent, lipid-peroxidation-driven cell death—as a potential upstream driver linking metabolic injury to inflammation and oncogenic transformation.
Why is this review important?
Mechanisms connecting metabolic stress to MASH-related HCC remain incompletely understood.
Ferroptosis may initiate inflammation rather than simply occur as a consequence of liver injury.
Understanding this pathway could identify patients at risk and reveal new therapeutic targets.
Key Takeaways:
Hepatocyte ferroptosis releases damage-associated molecular patterns, activating myeloid cells and inflammatory cytokines.
Inflammation can reciprocally promote Kupffer-cell ferroptosis, creating a self-amplifying injury cycle.
A proposed four-gene signature—FABP4, CAPG, QSOX1 and FXN—may characterize progression from metabolic stress to tissue remodelling.
Polyunsaturated fatty acids can shift from physiological signalling molecules to ferroptotic substrates when antioxidant defenses fail.
PNPLA3, TM6SF2 and MBOAT7 variants may increase susceptibility to this lipid-peroxidation environment.
Sex-related differences in iron handling and ferroptosis may contribute to different MASH progression risks.
Persistent ferroptosis–immune activation may create an inflammatory environment favoring fibrosis and HCC development.
Targeting ferroptosis could potentially interrupt MASH progression before irreversible fibrosis or oncogenic transformation.
What Does This Review Add?
It reframes MASH progression as a ferroptosis ↔ immune activation loop, integrating metabolic stress, genetic susceptibility, inflammation, fibrosis, and HCC within one mechanistic model.
Bottom Line:
Ferroptosis may be a key mechanistic bridge connecting metabolic injury, inflammation, and MASH-related HCC. Targeting the ferroptosis–immune axis is promising, but remains a translational rather than established clinical strategy.
