PLIN3: a multifaceted regulator of lipid droplet dynamics and disease pathogenesis

Lipids, as core membrane components, energy stores, and signaling molecules, are indispensable for homeostasis; their dysregulation drives obesity, type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Lipid droplets (LDs), originating from the endoplasmic reticulum, are phospholipid-monolayer-enclosed organelles that dynamically interact with mitochondria and peroxisomes, buffering lipotoxicity, sequestering bioactive lipids, and facilitating enzymatic reactions-positioning them as metabolic hubs. PLIN3, a PAT family protein, uniquely regulates LD formation/stabilization andmediates mannose 6-phosphate receptor (MRP) trafficking: its dysfunction links to cancer (amplified growth factor receptor recycling), neurodegeneration (impaired α-synuclein clearance), and metabolic syndrome (hepatic cholesterol retention). This review synthesizes PLIN3's structural features, LD-centric roles, and non-canonical MRP transport, establishing it as a critical node bridging lipid homeostasis and disease, with implications for therapeutic targeting in metabolic, oncologic, and neurodegenerative conditions.