Lipid Droplets as Metabolic–Epigenetic Signaling Hubs: Interplay Between Phase Separation, Cellular Adaptation, and Disease

Lipid droplets (LDs) were long thought to be passive organelles merely for neutral lipid storage. Mounting evidence redefines LDs as dynamic metabolic signaling hubs orchestrating cellular stress adaptation, with multifaceted roles in organelle crosstalk, metabolic reprogramming, redox balance and immune signaling. LD function is tightly intertwined with liquid–liquid phase separation (LLPS) and epigenetic remodeling, bridging cellular metabolism to gene expression and cell fate control. LD biogenesis relies on ER lipid structures, phase-separated protein assemblies and lipid regulatory proteins. Via contacts with multiple organelles, LDs regulate lipid catabolism, ferroptosis, inflammation and chromatin accessibility, while their metabolites directly reshape epigenetic modifications and transcription. LLPS-driven biomolecular condensates further coordinate LD-linked metabolic and stress signaling. Dysregulated LD remodeling mediates metabolic flexibility, immune escape and drug resistance in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, viral infection and cancer. This review summarizes progress in LD biogenesis and metabolism, dissects mechanistic crosstalk between LDs, LLPS and epigenetic control, and outlines LD-driven pathogenic reprogramming across human disorders. We also discuss therapeutic approaches targeting LD and LLPS pathways. Despite promising translational prospects, unresolved mechanistic and clinical hurdles persist. Further research on LD biology will reshape our framework linking metabolism, chromatin regulation and stress adaptation.