Lipophagy in disease: signaling control, organelle communication, and therapeutic opportunities.

Lipid droplet (LD) accumulation and impaired lipid mobilization induce lipotoxic stress and contribute to metabolic, cardiovascular, cancer, and neurodegenerative diseases (NDDs). Although LD-selective autophagy (lipophagy) is being increasingly studied, the mechanisms that confer LD specificity and enable tissue- and stage-specific therapeutic modulation remain unclear. Effective lipophagic flux requires coordinated LD coat remodeling, nutrient and energy sensing, and organelle contact. Coat remodeling governs substrate access and droplet recognition. The AMPK-mTORC1-TFEB axis links autophagy induction to lysosome biogenesis and capacity. Endoplasmic reticulum (ER)-LD, mitochondria-LD, and LD-lysosome contact sites facilitate lipid transfer by coupling lysosomal hydrolysis to mitochondrial β-oxidation. Lipophagy is a highly stage- and cell-type-dependent process: it removes excess lipids to protect cells, but its dysregulation can promote inflammation and fibrogenesis or supply substrates to tumors. This review synthesizes mechanistic and translational evidence on lipophagy initiation, regulation, and disease relevance, and identifies the following priorities: robust biomarkers, distinction of cargo-recognition defects from lysosomal dysfunction, and precision interventions tailored to the tissue and disease stage.