Abstract
Ferroptosis is recently reported as a new mode of regulated cell death. It is triggered by disturbed redox homeostasis, overloaded iron and increased lipid peroxidation. Howerver, the role of ferroptosis in hepatic fibrosis remains obscure. In the current study, we attempted to investigate the effect of Magnesium isoglycyrrhizinate (MgIG) on ferroptosis in liver fibrosis, and to further clarify the possible mechanisms. Our data showed that MgIG treatment markedly attenuated liver injury and reduced fibrotic scar formation in the rat model of liver fibrosis. Moreover, experiments in vitro also confirmed that MgIG treatment significantly decreased expression of hepatic stellate cell (HSC) activation markers. Interestingly, HSCs treated by MgIG presented morphological features of ferroptosis. Furthermore, MgIG treatment remarkably induced HSC ferroptosis by promoting the accumulation of iron and lipid peroxides, whereas inhibition of ferroptosis by specific inhibitor ferrostatin-1 (Fer-1) completely abolished MgIG-induced anti-fibrosis effect. More importantly, our results determined that heme oxygenase-1 (HO-1) was in the upstream position of MgIG-induced HSC ferroptosis. Conversely, HO-1 knockdown by siRNA evidently blocked MgIG-induced HSC ferroptosis and in turn exacerbated liver fibrosis. Overall, our research revealed that HO-1 mediated HSC ferroptosis was necessary for MgIG to ameliorate CCl4-induced hepatic fibrosis.