Calcitriol Inhibits NaAsO2 Triggered Hepatic Stellate Cells Activation and Extracellular Matrix Oversecretion by Activating Nrf2 Signaling Pathway Through Vitamin D Receptor

Previous studies, including our own, have demonstrated that arsenic exposure can induce liver fibrosis, while the underlying mechanism remains unclear and there is currently no effective pharmacological intervention available. Recent research has demonstrated that vitamin D supplementation can ameliorate liver fibrosis caused by various etiologies, potentially through modulation of the Nrf2 signaling pathways. However, it remains unclear whether vitamin D intervention can mitigate arsenic-caused liver fibrosis. As is known hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition are pivotal in the pathogenesis of liver fibrosis. In this study, we investigated the intervention effect of calcitriol (a form of active vitamin D) on arsenite-triggered Lx-2 cells (a human hepatic stellate cell line) activation and ECM oversecretion. Additionally, we also elucidated the role and mechanism of Nrf2 antioxidant signaling pathway. Our results demonstrated that calcitriol intervention significantly inhibits Lx-2 cell activation and ECM oversecretion induced by arsenite exposure. Additionally, calcitriol activates Nrf2 and its downstream antioxidant enzyme expression in Lx-2 cells, thereby reducing ROS overproduction caused by arsenite exposure. Further investigation reveals that calcitriol activates the Nrf2 signaling pathway and inhibits arsenite-triggered Lx-2 cell activation and ECM oversecretion by targeting vitamin D receptor (VDR). In conclusion, this study has demonstrated that vitamin D intervention can effectively inhibit HSC activation and ECM oversecretion triggered by arsenite exposure through its antioxidant activity. This provides a novel strategy for targeted nutritional intervention in the treatment of arsenic-induced liver fibrosis.