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 enhances autophagic flux but impairs degradation. ATG9A disrupted hepatic lipid metabolism: it reduced lipid droplet accumulation but exacerbated inflammation and fibrosis. Furthermore, we identified PLA2G6 as a fresh 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 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.