YAP promotes fibrosis by regulating macrophage to myofibroblast transdifferentiation and M2 polarization in chronic pancreatitis

Chronic pancreatitis (CP) is a clinical entity characterized by progressive inflammation and irreversible fibrosis of the pancreas, which ultimately leads to exocrine and/or endocrine insufficiency as well as an increased risk of pancreatic cancer. Currently, there are no specific or effective approved therapies for CP. Herein, we show that macrophage to myofibroblast transdifferentiation (MMT) and M2 macrophage polarization are associated with both human CP and CP experimental mouse models. In addition, we show YAP is activated in macrophages during CP. Furthermore, we used the YAP agonist XMU-MP-1 (XMU) and the YAP inhibitor Verteporfin (VP) to modulate YAP expression levels. In vitro experiments revealed that XMU upregulated YAP expression, thereby promoting MMT and enhancing M2 macrophage polarization; conversely, VP downregulated YAP expression, inhibiting these effects. In vivo studies indicated that XMU exacerbated acinar cell atrophy and interstitial fibrosis in caerulein-induced mouse models of CP, while VP mitigated these adverse effects associated with CP. These findings provide new insights into the pathogenic mechanisms underlying CP, and offer potential therapeutic targets for CP.