Metabolic dysfunction-associated steatohepatitis (MASH) represents a major global health burden, bridging isolated steatosis, progressive fibrosis and hepatocellular carcinoma. Recent paradigms highlight ferroptosis, an iron-dependent, lipid-peroxidation-driven form of regulated cell death, as a primary lytic initiating event in metabolic liver injury. In this review, we delineate the ferroptosis-immune axis in MASH, characterising it as a self-amplifying, bidirectional circuit. In this framework, parenchymal ferroptotic rupture and damage-associated molecular pattern emission drive myeloid activation and pro-inflammatory cytokine release. This inflammatory microenvironment reciprocally triggers cell-autonomous Kupffer cell ferroptosis and homeostatic collapse. We establish a novel cell-type-specific transcriptomic framework governed by a core four-gene signature (FABP4, CAPG, QSOX1 and FXN) that maps the transition from early metabolic stress to advanced structural remodelling. Furthermore, we decode the substrate paradox of polyunsaturated fatty acids, illustrating how their role shifts from physiological signalling to executioner substrates when antioxidant systems collapse. This biophysical vulnerability is heavily primed by inherited gene polymorphisms, including PNPLA3, TM6SF2 and MBOAT7. By evaluating the sexual dimorphism embedded within these pathways, specifically how the DTL-PROX1 axis dictates distinct iron accumulation rates and lipid peroxidation sensitivities, we propose precise clinical stratification strategies. Finally, we outline actionable translational avenues, highlighting how targeting the ferroptosis-immune axis offers a highly specific therapeutic window to arrest lipotoxicity, suppress inflammation and disrupt oncogenic priming before irreversible tissue remodelling occurs.
