Lipid-Droplet Remodeling in Hepatic Stellate Cells in Liver Fibrosis: An Evidence-Tiered Synthesis of Lipophagy, Retinoid Metabolism, and Organelle Crosstalk

In quiescent hepatic stellate cells (HSCs), lipid droplets (LDs) constitute specialized retinoid-rich storage organelles. Upon hepatic injury, various characteristics of LDs—including their abundance, size, composition, retinoid storage capacity, mobilization dynamics, metabolic flux, and associated cell signaling pathways—undergo significant alterations. Current evidence does not support the notion that the visible loss of LDs alone constitutes a uniform or sufficient mechanism driving fibrogenic activation of HSCs. This review distinguishes the machinery that maintains retinoid-rich LD identity from activation-associated lipid mobilization and from organelle relationships that remain primarily functional or inferential. We emphasize the roles of lecithin retinol acyltransferase (LRAT) and retinol-binding protein 1 (RBP1) in retinoid metabolism, compare candidate cytosolic hydrolases with lysosome-dependent lipid mobilization pathways, and differentiate evidence derived directly from HSCs from findings based on broader liver context or general LD biology. We propose an integrated, multidimensional model of HSC LD remodeling, suggesting that therapeutic interventions should target the establishment of a defined, less fibrogenic HSC phenotype rather than merely modulating LD quantity.