Gambogic Acid suppresses Pancreatic Fibrosis via Inhibiting YAP1-mediated Activation of Pancreatic Stellate Cells

Activation of pancreatic stellate cells (PSC) and the secretion of inflammatory factors are crucial in pancreatic fibrosis. Gambogic acid (GA), a flavonoid with antitumor properties, has an unclear role in this process. Our study found that GA promotes YAP1 degradation and reduces its nuclear localization, thereby inhibiting PSC activation and the development of pancreatic fibrosis. GA inhibits proliferation, decreases α-SMA expression, and reduces lipid droplets in LTC14 and primary mouse pancreatic stellate cells (mPSC). GA inhibits inflammatory factors (NLRP3, Nrf2, IL-6, TNF-α, and NF-κB) in PSC and reverses the TGF-β-induced increase in these proteins. GA also decreases Collagen I and TIMP1 expression, thereby inhibiting fibrosis. Furthermore, we demonstrated that GA reduces YAP1 expression and its nuclear translocation, while also counteracting the TGF-β-induced increase in YAP1 expression. The overexpression of YAP1 counteracts the inhibitory effects of GA on PSC activation and inflammation. Additionally, GA activates the Hippo pathway, elevates p-LATS1 and p-YAP levels, and promotes the ubiquitin-mediated degradation of YAP1. In vivo studies also confirmed that GA inhibits dibutyltin dichloride (DBTC)-induced pancreatic fibrosis via inhibiting YAP1 and NF-κB in BALB/c mice. In summary, GA activates the Hippo pathway, promotes YAP1 translocation to the cytoplasm, leading to its degradation, and thereby inhibits PSC activation and fibrosis. Our research highlights the significance of ubiquitin-mediated YAP1 degradation in inhibiting PSC activation and offers a fresh perspective on the molecular foundation for developing GA as a potential treatment for pancreatic fibrosis.