Lipophagy Mitigates Radiation-induced Liver Lipid Disorders and Damage in Adolescent Mice

Ionizing radiation poses a significant health risk to adolescent livers by disrupting lipid metabolism, yet protective mechanisms remain poorly understood. We investigated this using a pubertal mouse model exposed to localized X-irradiation. Our approach combined transcriptomics, lipidomics, and pharmacological modulation of lipophagy with 3-methyladenine and rapamycin. We also introduced a high-fat diet (HFD) to explore its synergistic effects with radiation. Radiation exposure alone reduced liver mass, increased plasma transaminases [Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], caused intrahepatic lipid droplet retention, and impaired glucose tolerance. Lipidomics revealed significant accumulation of lysophosphatidylcholine, triglycerides, and diacylglycerols. Notably, combining high-fat diet with radiation synergistically worsened mild radiation-induced steatosis into severe hepatocellular damage, with sharply increased transaminases and insulin resistance. Mechanistically, radiation down-regulated key lipophagy-related genes like ATGL and LC3B-II. Pharmacological inhibition of lipophagy worsened steatosis and liver dysfunction, while its activation improved lipid clearance and considerably reduced liver injury. Our findings establish lipophagy as a vital adaptive response to radiation-induced metabolic stress in the adolescent liver. This study highlights the combined toxic effects of environment and diet and suggests that boosting lipophagy could be an effective strategy to lessen the adverse health effects of radiation exposure in vulnerable young populations.