Liver-specific loss of perturbs lipid metabolism and hepatocyte integrity.

The autophagy-related protein ATG9A is integral to cellular autophagy and lipid mobilization, yet its importance in mammalian physiology remains underexplored. Using a liver-specific conditional knockout (-cKO) mouse model, we uncovered critical insights into the physiological function of ATG9A in this organ. -cKO mice exhibited hepatomegaly, abnormal hepatocyte morphology, mitochondrial fragmentation, and lipid droplet accumulation. Blood chemistry and proteomics analyses revealed elevated serum cholesterol, reduced albumin, and dysregulation of pathways related to lipid metabolism and oxidative stress responses. These findings establish an essential role for ATG9A in maintaining hepatocyte integrity, lipid trafficking, and overall liver health, offering a model for studying autophagy-related hepatic pathologies.