SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis.

SGLT2 is overexpressed in various cancers, including pancreatic cancer. However, the mechanisms underlying the tumorigenic effects of SGLT2 in pancreatic cancer remain unclear. In this study, we demonstrated that SGLT2 inhibition significantly suppressed the growth of pancreatic cancer cells in vitro and in vivo. RNA sequencing, real-time PCR, and Western blot analyses revealed that SGLT2 silencing or inhibition suppressed Hippo signaling activation by downregulating YAP1 expression. Liquid chromatography-mass spectrometry and immunoprecipitation analyses showed that SGLT2 interacted with hnRNPK, promoting its nuclear translocation and thereby enhancing hnRNPK-induced YAP1 transcription. Importantly, YAP1 inhibitor enhanced the anti-pancreatic cancer effect of SGLT2 inhibitor in mice bearing pancreatic tumors. These findings suggest that SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway through the hnRNPK-YAP1 axis. Hence, SGLT2 inhibition alone or combined with YAP1 inhibition may represent a promising therapeutic approach for pancreatic cancer.