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

ABSTRACT:

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.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS12451 | MetaboLights | 2025-10-24

REPOSITORIES: MetaboLights

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			Action	DRS
	neg_20240592_AAV-1.mzXML	Mzxml
	neg_20240592_AAV-1.wiff	Wiff
	neg_20240592_AAV-1.wiff.scan	Wiff
	neg_20240592_AAV-2.mzXML	Mzxml
	neg_20240592_AAV-2.wiff	Wiff

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