Rab7 is identified as a key activator of starvation-induced lipophagy in primary mouse hepatocytes; its regulation in overnutrition models (e.g., HFD) remains unclear. Acute lipid overload mouse models and ex vivo human liver tissue reveal mTORC1 initiates lipophagy by phosphorylating Plin3. MASLD patient livers show reduced LAMP2A, Plin5 accumulation, and impaired CMA function. This evidence concerns the gene PLIN5 and metabolic dysfunction-associated steatotic liver disease.