Fig. 3

The regulatory mechanisms of ferroptosis in MASLD and its effects on the progression of MASLD. Cystine enters the cell via SLC7A11 and SLC3A2 embedded in the surface of the cell membrane and is then oxidized to cysteine, which is catalytically synthesized into GSH.GPX4 utilizes the ability of GSH to convert lipid peroxidation of L-OOH to L-OH, losing its peroxidative activity and thus protecting against the induction of ferroptosis. Nrf2 inhibits ferroptosis by regulating GPX4 and iron metabolism. PUFA binds to phosphatidylethanolamine(PE) to form polyunsaturated fatty acids phospholipids, the latter of which are susceptible to lipoxygenase(LOX)-mediated free radical-induced oxidation that induces ferroptosis. Fe3 + is uptaken by TFR1, reduced to Fe2 + by STEAP3, and later transported into the cytoplasmic unstable iron pool (LIP), a regulator of iron metabolism, and two proteins in the family of zinc-iron-modulated proteins (ZIP8/14), however, in the presence of excess Fe2+, can induce cellular ferroptosis by increasing reactive oxygen species generation and promoting lipid peroxidation formation via the fenton pathway. GSH, glutathione; GPX4, glutathione peroxidase 4; Nrf2, nuclear erythroid-related factor 2; PUMA, P53-up-regulated modulator of apoptosis; TFR1, transferrin receptor 1

P53-up-regulated modulator of apoptosis; TFR1, transferrin receptor 1