Canagliflozin inhibits hepatic stellate cells activation and proliferation by inhibiting PP2A-mediated β-catenin dephosphorylation to attenuate hepatic fibrosis

Hepatic fibrosis (HF) is a leading cause of death worldwide, yet there is currently no safe and effective treatment available. Canagliflozin, a novel glucose-lowering drug, has been shown to improve non-alcoholic steatohepatitis (NASH). However, its therapeutic effects on HF and the underlying molecular mechanisms remain unclear. In this study, HF was induced in mice via intraperitoneal injections of CCl 4 . Additionally, immortalized hepatic stellate cells (HSCs), including HSC-T6 and LX-2 cells, were used for in vitro experiments. Our findings revealed that Canagliflozin inhibited the activation and proliferation of HSCs, thereby downregulated the expression levels of fibrotic markers (α-SMA and Collagen I), ultimately alleviating HF. Further investigations demonstrated that Canagliflozin inhibits protein phosphatase 2 A (PP2A) activity in HSCs, which in turn prevents PP2A-mediated dephosphorylation of β-catenin and attenuates Wnt/β-catenin signaling. While the Wnt/β-catenin signaling is considered a key mechanism that promote the activation and proliferation of HSCs, it is also a crucial pathway in the development of HF. Moreover, increased activity of PP2A was found to promote the expression of fibrotic markers (α-SMA and Collagen I) in HSCs. In conclusion, our study indicates that Canagliflozin ameliorate HF via inhibiting PP2A-mediated dephosphorylation of β-catenin in HSCs. The inhibition of PP2A in HSCs may represent a potential therapeutic target not only for cancer treatment but also for the management of HF.