OSBPL2 deficiency alleviates diet-induced MASLD by reducing ACSL4-mediated ferroptosis

Oxysterol-binding protein-like 2 (OSBPL2) is a lipid transfer protein that modulates intracellular lipid homeostasis; however, its regulatory role in coordinating iron and fatty acid homeostasis remains largely elusive. A recent study has reported a strong positive correlation between iron overload and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we found that OSBPL2 binds to HSP90β, and OSBPL2 deficiency inhibits ACSL4 expression while altering hepatic fatty acid distribution by impairing lipolysis. Depletion of OSBPL2 conferred resistance to ferroptosis via the ACSL4-mediated ferroptosis pathway and further attenuated diet-induced liver fibrosis in mice. Our findings provide important insights into the function of OSBPL2 in ferroptosis and suggest that OSBPL2 may serve as a potential therapeutic target for MASLD.