ATG9A-PLA2G6 axis reprograms phospholipid metabolism to drive metabolic liver disease and hepatocellular carcinoma.

The liver orchestrates systemic metabolism, and its dysfunction drives diseases including metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). ATG9A, an autophagy-related transmembrane protein and lipid scramblase, regulates lipid dynamics, yet its role in hepatic pathogenesis remains unclear. Using multi-model approaches, we demonstrate that liver-specific ATG9A overexpression in mice enhanced autophagic flux but impaired autophagosome degradation. ATG9A disrupted hepatic lipid metabolism, reduced lipid droplet accumulation and exacerbated inflammation and fibrosis. Furthermore, we identified PLA2G6 as an ATG9A binding protein. ATG9A-PLA2G6 interaction accelerated phosphatidylcholine degradation, perturbing fatty acid metabolism and causing mitochondrial dysfunction. Besides, ATG9A promoted tumor growth in vivo, independent of canonical macroautophagy/autophagy. Our findings redefine ATG9A as a dual metabolic effector, driving liver disease progression through lipid remodeling and organelle stress. The ATG9A-PLA2G6 axis presents a therapeutic target for metabolic liver disorders and HCC.