ATGL-LC3B-Lipid Complexes Mediate Lipophagy-Driven Radioprotection Against Metabolic Liver Injury in Adolescents

Radiation-induced liver disease (RILD) poses a significant clinical challenge, particularly in adolescents with hepatocellular carcinoma, where mortality exceeds 70%. Radiation disrupts lipid-protein homeostasis, but its interaction with selective autophagic pathways such as lipophagy, a lipid droplet degradation process critical for metabolic balance, remains unexplored in adolescent mice. Using pubertal mice exposed to 6 Gy whole-body X-rays, we integrated transcriptomics, lipidomics, and functional assays to dissect radiation-induced hepatic injury. Multi-omics analyses revealed three hallmarks of macromolecular dysregulation: (1) Hepatocellular damage (reduced organ index, elevated AST/ALT, histopathological lesions); (2) Lipotoxicity driven by lysophosphatidylcholine/triglyceride/diacylglycerol accumulation; and (3) Lipophagy suppression via downregulation of ATGL and LC3B-II, key regulators of lipid droplet-lysosome fusion. Mechanistically, ATGL-LC3B-II-lipid complexes were identified as radioprotective hubs maintaining lipid homeostasis. Pharmacological inhibition of lipophagy (3-MA) exacerbated radiation-induced steatosis and liver dysfunction, whereas activation (Rapamycin) restored lipid clearance. These findings align with clinical evidence linking lipophagy defects to chemotherapy-associated fatty liver. Targeting lipophagy enhancers (e.g., zinc, FOXO1 activators) may mitigate radiotherapy-induced metabolic toxicity, offering novel therapeutic strategies for RILD in vulnerable populations. Our study establishes lipophagy as a central adaptive response to radiation-driven metabolic stress, bridging molecular mechanisms with clinical translation.