Lipophagy in metabolic diseases: mechanisms, organelle crosstalk, and nanotherapeutic opportunities

Lipophagy, the selective autophagic degradation of lipid droplets via the lysosomal pathway, has emerged as a central homeostatic mechanism against lipotoxicity in multiple organ systems. This review provides a comprehensive synthesis of lipophagy, including macrolipophagy, microlipophagy, and chaperone-mediated autophagy (CMA)-lipophagy, with particular emphasis on the AMPK-mTORC1-TFEB regulatory axis and Plin protein ubiquitination as critical control nodes. Furthermore, this review delineates the functional crosstalk between lipophagy and neutral lipolysis in maintaining lipid homeostasis. Lipophagy dysfunction also has pathogenic implications in some metabolic diseases. Notably, recent progress in nanoparticle-based delivery systems enables tissue-specific lipophagy modulation with enhanced efficacy and reduced off-target toxicity. However, challenges related to cell-type specificity, narrow therapeutic windows, and disease heterogeneity remain. Context-dependent dosing will therefore be needed to bridge the gap between lipophagy-targeted interventions and clinical application in hyperlipidemia-related metabolic diseases is necessary.