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.

肝脏是全身代谢的调控中枢，其功能异常可引发包括代谢功能障碍相关脂肪性肝病（metabolic dysfunction-associated steatotic liver disease, MASLD）与肝细胞癌（hepatocellular carcinoma, HCC）在内的多种疾病。ATG9A作为一种自噬相关跨膜蛋白与脂质 scramblase，可调控脂质动态平衡，但其在肝脏发病机制中的作用尚未明确。本研究通过多模型方法证实，在小鼠体内实现肝脏特异性ATG9A过表达可增强自噬流，但会损伤自噬体的降解过程；ATG9A可扰乱肝脏脂质代谢，减少脂滴蓄积，并加剧炎症反应与纤维化进程。此外，本研究鉴定出PLA2G6是ATG9A的结合蛋白，二者的相互作用可加速磷脂酰胆碱的降解，扰乱脂肪酸代谢并引发线粒体功能异常。同时，ATG9A可在体内促进肿瘤生长，且该过程不依赖经典巨自噬/自噬通路。本研究结果将ATG9A重新定义为一种双重代谢效应因子，通过脂质重塑与细胞器应激推动肝脏疾病的进展；ATG9A-PLA2G6轴可为代谢性肝病与肝细胞癌提供潜在治疗靶点。