Ferroptosis is a form of non-apoptotic cell death driven by iron-dependent lipid peroxidation (LPO). Ferroptosis is closely associated with hepatic metabolic pathways, particularly those involving iron, fatty acids, amino acids, and redox changes. This review aims to provide a comprehensive overview of the current molecular pathways and regulatory mechanisms underlying iron homeostasis and intracellular compartmentation in liver biology, emphasizing the roles of ferroptosis in several liver diseases, such as ischemia-reperfusion injury, drug-induced liver injury, viral hepatitis, metabolic dysfunction–associated steatotic liver disease, alcohol-associated liver disease, fibrosis, and hepatocellular carcinoma. We have also discussed the challenges of interpreting ferroptosis-related data, proposed a framework for defining ferroptosis, and highlighted future research directions as well as the therapeutic potential of targeting ferroptosis in the treatment of various liver diseases.

Metabolic dysfunction-associated steatohepatitis (MASH) is the inflammatory phase of the metabolic dysfunction-associated steatotic liver disease (MASLD) spectrum, and can progress to fibrosis and even carcinoma; currently, there are few effective therapies. The complex branched glucose polymer glycogen is found in significant quantities in the liver; it comprises “β particles”, ~20 nm in size, bound as aggregate “α particles”, up to hundreds of nm in size. The role of liver glycogen in MASLD and MASH is unknown. Size-exclusion chromatography, fluorophore-assisted carbohydrate electrophoresis and transmission electron microscopy show that, compared with healthy controls, MASLD livers exhibited a higher β-particle content (32.6% vs 40.7%, P <0.05) and a 5 % longer average chain length (ACL); MASH amplified these defects: β-particle fraction rose to 46.1% (P <0.001 vs. control) and ACL to 26 % (P <0.0001 vs. control), indicating this is an early, shared disruption in different stages of MASLD. The glycogen-related proteins (AGL, GBE, GYS, PYGL and PPP1R3B) exhibit opposite trajectories in MASLD and MASH. Therapeutic dietary polyphenols, despite disparate effects on individual glycogen-related enzymes, all reversed aberrant glycogen architecture by increasing α-particle proportions and decreasing chain lengths. Our findings offer a mechanistic blueprint whereby glycogen structure characterization might guide clinical therapeutic strategy.