Mammalian lipophagy: process and function

Lipophagy, the selective autophagic degradation of lipid droplets (LDs), is a key mechanism for lipid homeostasis and cellular adaptation to metabolic and stress conditions. In mammals, lipophagy is governed by signaling pathways, LD-associated receptors (e.g. SQSTM1/p62, NBR1, OPTN, SPART, OSBPL8, DDHD2, VPS4A, ATG14, and TP53INP2), and transcription factors (TFEB, TFE3, FOXO1, PPARA, PPARG, and SREBF1/SREBP1) that coordinate LD recognition, sequestration, and lysosomal degradation. Dysregulated lipophagy contributes to the pathogenesis of metabolic and age-related diseases, including metabolic dysfunction-associated steatotic liver disease/nonalcoholic fatty liver disease (MASLD/NAFLD), alcoholic liver disease, diabetes, atherosclerosis, neurodegeneration and cancer. Several recent reviews have discussed lipophagy from different angles, including its roles in metabolic disorders, central nervous system diseases, and fundamental mechanisms across species. In contrast, this review focuses specifically on mammalian lipophagy by synthesizing the latest mechanistic insights into receptor-mediated recognition, transcriptional regulation, and signaling integration. We also outline unresolved questions and conceptual gaps - such as how lipophagy is selectively activated, how it coordinates with lipolysis, and whether distinct receptor codes exist in tissue- and disease-specific contexts - that remain unanswered in the current literature.<b>Abbreviations</b>: AMPK, AMP-activated protein kinase; ATG, autophagy related; ATG8s: mammalian Atg8-family proteins; C1P: ceramide-1-phosphate; CMA, chaperone-mediated autophagy; COPI, coatomer protein complex I; DENV, dengue virus; ER, endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; FFA: free fatty acid; HOPS, homotypic fusion and vacuole protein sorting; LDs, lipid droplets; LIR: LC3-interacting region; MASLD, metabolic dysfunction-associated steatotic liver disease; MTORC1: mechanistic target of rapamycin kinase complex 1; PE: phosphatidylethanolamine; PEDV: porcine epidemic diarrhea virus; PENV, porcine epidemic diarrhea virus; PtdIns3K-C1: class III phosphatidylinositol 3-kinase complex 1; PtdIns3P, phosphatidylinositol-3-phosphate; ROS, reactive oxygen species; SNARE: soluble NSF attachment protein receptor; SPG54: spastic paraplegia type 54; TAG: triacylglycerol/triglyceride; UBDs, ubiquitin-binding domains.