Targeting ferroptosis to halt MASLD and MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic, with its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), driving cirrhosis and hepatocellular carcinoma. Ferroptosis, an iron-dependent form of programmed cell death, is a central pathogenic mechanism in MASLD and MASH. The core drivers of ferroptosis include dysregulated iron metabolism, an increase in peroxidation-susceptible phospholipids, and impaired antioxidant defenses. These changes promote hepatocyte death via a so-called 'ferroptotic explosion' triggered by an increase in FerroLipid, thus driving the transition from a profibrotic state to overt fibrosis. Notably, targeting ferroptosis with iron chelators and ferroptosis inhibitors shows promise as a therapeutic strategy by restoring redox and lipid homeostasis. Furthermore, systemic crosstalk between the liver, adipose tissue, and gut microbiota modulates ferroptotic susceptibility, revealing new avenues for developing precision-targeted therapies.