 This study evaluated the effects of extracellular vesicles from placenta-derived mesenchymal stem stromal cells, PDMSC-SEVS, on liver fibrosis at 3D-2D levels and explored the potential mechanisms. PDMSC-SEVS significantly alleviated fibrotic phenotypes in liver organoids and HSCs models, with MIR-378C identified as a potential key anti-fibrosis content. Exosomal-MIR-378C inactivated HSCs by inhibiting epithelial mesenchymal transition, EMT, through stabilizing e-caterin via targeting its E3 ubiquitin ligase S-phase kinase associated protein 2, SKP2. PDMSC-SEVS may be an efficient therapeutic candidate for liver fibrosis. This article was authored by Wenjiexian, Tsaiyang-Bien, Xuqiu, and others.