Targeting Sphingosine-1-Phosphate Receptor 2 Attenuates Clonorchis sinensis-Induced Biliary Injuries

This study reveals that chronic Clonorchis sinensis (Cs) infection activates the sphingolipid metabolic pathway, particularly the sphingosine-1-phosphate (S1P) / sphingosine 1-phosphate receptor 2 (S1PR2) signaling axis, which plays a central role in driving biliary injury and cholangiocarcinoma development‌. Cs infection causes persistent epithelial damage and bile duct obstruction, leading to metabolic reprogramming and microbial imbalance. Using multi-omics approaches, researchers found that the S1P generation pathway is significantly activated in the hepatobiliary tissues of infected mice. Biliary epithelial cells (BECs), the first line of defense against Cs, show upregulated expression of S1PR2 during infection. In vivo experiments using wild-type and S1PR2 knockout mice demonstrated that S1PR2 is predominantly expressed in BECs, and its absence markedly reduces Cs-induced biliary pathology, epithelial hyperplasia, and periductal fibrosis. In vitro, stimulation of BECs with Clonorchis sinensi excretory-secretory products (CsESPs), taurine bile acid, or S1P activates the ERK1/2 and p65 signaling pathways-effects that are effectively blocked by the S1PR2 antagonist JTE-013. These findings highlight that S1PR2 signaling is a key mediator of Cs-induced biliary damage and suggest that targeting this pathway could offer a promising therapeutic strategy for preventing or treating infection-related cholangiocarcinoma.