The bile acid TUDCA promotes chemoresistance and predicts survival through MAPK signaling in pancreatic ductal adenocarcinoma.

Our study comprehensively investigated the prognostic significance and biological mechanisms of bile acids in patients with advanced pancreatic adenocarcinoma (PC) through clinical data analysis, in vitro cell assays, and in vivo xenograft models. A total of 101 patients with advanced pancreatic adenocarcinoma were followed up in this study. Multivariate Cox regression identified elevated total bile acids (tBA) as an independent risk factor for progression-free survival (PFS). Patients with high tBA exhibited significantly shorter PFS and overall survival (OS), alongside impaired liver function and an immunosuppressive profile. Bile acid mass spectrometry further identified tauro-ursodeoxycholic acid (TUDCA) as a key subtype strongly associated with poor survival and a diminished response to first-line gemcitabine-based chemotherapy. ROC analysis confirmed that TUDCA outperformed tBA and other clinical indicators in predicting treatment outcomes. Mechanistically, TUDCA did not affect pancreatic cancer cell proliferation but significantly attenuated gemcitabine-induced cytotoxicity both in vitro and in vivo by inhibiting apoptosis. RNA sequencing and western blot analyses revealed that TUDCA confers chemoresistance by activating the MAPK signaling pathway. Notably, the MEK1/2 inhibitor trametinib successfully reversed TUDCA-mediated resistance in experimental models. These findings identify TUDCA as a novel prognostic biomarker and a potential therapeutic target to enhance chemotherapy efficacy in advanced PC.