ASIC1a regulates ferroptosis in hepatic stellate cells via the Hippo/Yap-1 pathway in liver fibrosis

Background: Liver fibrosis is a sustained process of liver tissue damage and repair caused by various physiological and pathological factors, with the activation and proliferation of hepatic stellate cells being central. Therefore, understanding and clarifying the relevant mechanisms of hepatic stellate cell activation and death is of great clinical significance for the treatment of liver fibrosis diseases.

Methods: In vivo, recombinant adeno-associated virus was used to infect the liver of experimental mice, overexpressing ASIC1a, and based on this, a liver fibrosis model treated with sorafenib was constructed. In vitro, using RNA plasmid technology to transfect HSC-T6 cells, ASIC1a was overexpressed or silenced in the cells, and on this basis, PDGF-BB and Sorafenib were used to stimulate HSC-T6 cells, causing activated HSC-T6 to undergo Ferroptosis.

Results: The Ferroptosis inducers Sorafenib and erastin can induce Ferroptosis in HSCs, effectively inhibiting or reversing the progression of liver fibrosis. We found that the expression level of ASIC1a was significantly reduced in the livers of mice with liver fibrosis treated with Sorafenib. After treatment with an adeno-associated virus overexpressing ASIC1a, the therapeutic effect of Sorafenib was inhibited, and the level of Ferroptosis induced by Sorafenib was also inhibited. The induction of Ferroptosis in hepatic stellate cells in vitro depends on the presence of ASIC1a. By further exploring the potential mechanism, we observed that the overexpression of ASIC1a can promote an increase in YAP nuclear translocation, thereby regulating the activity of Hippo/YAP pathway signaling. After treatment with Sorafenib, the influx of CA²⁺ significantly increased when ASIC1a was overexpressed, and BAPTA-AM intervention eliminated the intracellular CA²⁺ accumulation induced by ASIC1a overexpression.

Conclusions: This indicated that the activation of YAP depends on the calcium ion influx induced by ASIC1a, which regulates Ferroptosis in hepatic stellate cells by regulating the calcium ion-dependent Hippo/YAP pathway.

ASIC1a; Ferroptosis; HSCs; Hippo/YAP pathway; Liver fibrosis.