Ferroptosis in metabolic dysfunction-associated steatotic liver disease.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread chronic liver disease that can progress from steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Its pathogenesis involves lipotoxicity, iron metabolism disorders, and oxidative stress-the same three processes that underlie ferroptosis, an iron-dependent form of regulated cell death mediated by the peroxidation of membrane phospholipids. However, the question of whether ferroptosis is a universal mechanism underlying the progression of MASLD as a whole or a hallmark of a distinct subgroup of patients remains unresolved. Furthermore, no ferroptosis-targeted strategy has yet been tested in a biomarker-selected population. This review addresses precisely this gap. Clinical, transcriptomic, and experimental data allow us to conceptualize hepatic ferroptosis as four interacting molecular modules: expansion of the labile pool of ferrous iron, enrichment of membranes with oxidizable polyunsaturated phospholipids, enzymatic and non-enzymatic lipid peroxidation, and failure of antioxidant defense. An imbalance in these modules leads to the accumulation of phospholipid hydroperoxides, disruption of membrane integrity, and immunogenic hepatocyte death with the release of signals that promote inflammation and fibrogenesis. At the same time, ferroptosis exhibits pronounced cellular and contextual specificity. It exerts a damaging effect on hepatocytes and sinusoidal endothelial cells, enhances inflammation in macrophages, but exerts an antifibrotic effect in activated stellate cells and immunosuppressive effects in lymphocytes. In this regard, known anti-ferroptotic strategies (iron chelation, inhibition of long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4)-dependent incorporation of polyunsaturated fatty acids, use of lipid radical scavengers and vitamin E, and activation of protective antioxidant programs) retain their diagnostic and therapeutic potential only within the framework of a molecularly and cell-stratified approach.