Mature Adipocyte‐Derived Extracellular Vesicles Activate Hepatic Stellate Cells and Promote Liver Fibrosis via Inflammation

Background and Aims Extracellular vesicles (EVs) play a crucial role in intercellular communication, particularly in metabolic regulation and liver disease. This study aimed to investigate the differential effects of EVs derived from pre‐adipocytes (PA) and mature adipocytes (MA) on hepatic stellate cell (HSC) activation in vitro and their role in promoting liver fibrosis in high‐fat diet (HFD)‐fed mice. Methods EVs were isolated from PA and MA following transdifferentiation, which was confirmed by assessing adipogenic markers (PPAR‐γ, perilipin, adiponectin, leptin, and Glut4). EVs were characterized by size and CD9 expression. LX‐2 cells were treated with PA‐ or MA‐derived EVs to assess fibrotic and inflammatory gene expression. In vivo, C57BL/6 mice on HFD were administered PA‐EVs or MA‐EVs to evaluate liver pathology. Results MA‐EVs exhibited a distinct transcriptomic profile and significantly upregulated fibrotic (α‐SMA, COL1A1) and inflammatory markers in LX‐2 cells, indicating HSC activation. Conversely, PA‐EVs had minimal effects. In HFD‐fed mice, MA‐EVs injection led to pronounced liver damage, including steatosis, inflammation, and fibrosis, compared with mice receiving PA‐EVs, which showed no major pathological changes. Conclusions MA‐EVs aggravate liver fibrosis and inflammation both in vitro and In vivo, while PA‐EVs appear to have relatively limited effects. These findings highlight the functional heterogeneity of adipocyte‐derived EVs and suggest MA‐EVs as potential contributors to the pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD). Targeting specific EV subpopulations may present novel therapeutic strategy for MASLD.