This study investigates the anti-fibrotic effects of mesenchymal stem cell (MSC)-derived exosomes (ExoMSC) in primary sclerosing cholangitis (PSC), an autoimmune liver disease characterized by chronic inflammation and fibrosis of the bile ducts. The research used Mdr2−/− mice and multicellular organoids derived from PSC patients to evaluate the therapeutic potential of ExoMSC. The results showed that ExoMSC significantly reduced liver fibrosis, as evidenced by decreased collagen levels and reduced Th17 cell infiltration. ExoMSC also inhibited Th17 differentiation, which is a key driver of fibrosis in PSC. The mechanism of action involves the regulation of the PERK/CHOP signaling pathway, which is involved in endoplasmic reticulum (ER) stress and apoptosis. ExoMSC treatment reduced the expression of fibrosis-related genes and improved the interaction between hepatic stellate cells (HSCs) and cholangiocytes, thereby ameliorating the fibrotic microenvironment. These findings suggest that ExoMSC have a promising therapeutic potential for PSC and other Th17-related diseases. The study highlights the importance of using advanced in vitro models, such as multicellular organoids, to better understand the complex pathophysiology of PSC and to develop effective treatments.This study investigates the anti-fibrotic effects of mesenchymal stem cell (MSC)-derived exosomes (ExoMSC) in primary sclerosing cholangitis (PSC), an autoimmune liver disease characterized by chronic inflammation and fibrosis of the bile ducts. The research used Mdr2−/− mice and multicellular organoids derived from PSC patients to evaluate the therapeutic potential of ExoMSC. The results showed that ExoMSC significantly reduced liver fibrosis, as evidenced by decreased collagen levels and reduced Th17 cell infiltration. ExoMSC also inhibited Th17 differentiation, which is a key driver of fibrosis in PSC. The mechanism of action involves the regulation of the PERK/CHOP signaling pathway, which is involved in endoplasmic reticulum (ER) stress and apoptosis. ExoMSC treatment reduced the expression of fibrosis-related genes and improved the interaction between hepatic stellate cells (HSCs) and cholangiocytes, thereby ameliorating the fibrotic microenvironment. These findings suggest that ExoMSC have a promising therapeutic potential for PSC and other Th17-related diseases. The study highlights the importance of using advanced in vitro models, such as multicellular organoids, to better understand the complex pathophysiology of PSC and to develop effective treatments.