INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally, leading to cirrhosis, hepatocellular carcinoma, and increased liver-related mortality, along with extrahepatic risks. A hallmark of MASLD is excessive neutral lipid accumulation in hepatocytes as cytosolic lipid droplets (LDs), which are now recognized as dynamic organelles involved in lipid storage, energy metabolism, signaling, and stress responses. Understanding LD pathobiology in MASLD is vital for insights into disease mechanisms and targeted therapies. AREAS COVERED: This review outlines current knowledge on LD biogenesis, growth, and turnover in hepatocytes and their disruption in MASLD. We discuss LDs' dual role as protective buffers against lipotoxicity and contributors to disease progression when lipid fluxes are altered. The involvement of LDs in non-parenchymal cells like hepatic stellate cells and macrophages in inflammation and fibrogenesis is examined. Human genetic studies linking LD-associated proteins (e.g. PNPLA3) to MASLD susceptibility are also discussed. EXPERT OPINION: LDs are crucial in MASLD pathogenesis, integrating genetic factors with metabolic signals. Future therapies should focus on normalizing lipid flux and LD functions rather than indiscriminately depleting them to avoid disrupting protective storage mechanisms.
Weiskirchen et al. (2026) studied this question.