MSC-EV PROTECTS AGAINST IMMUNOLOGICAL LIVER INJURY BY SUPPRESSING FERROPTOSIS VIA ACTIVATION OF THE NRF2/GPX4 SIGNAL AXIS

Ferroptosis plays an important role in the pathogenesis of various liver diseases, yet it has rarely been investigated in human autoimmune hepatitis (AIH). This study is meant to explore the protective effect and mechanism of extracellular vesicles of mesenchymal stem cells (MSC-EVs) on ferroptosis and excessive inflammation of immunological liver injury (ILI). We found that inflammation associated hepatocytes ferroptosis occurred in ILI mice, whereas deferoxamine attenuated liver injury. In ILI mice, MSC-EVs might reduce hepatocytes ferroptosis and subsequently improve liver injury, while KEGG pathways enrichment analysis also validated that ferroptosis inhibition was involved in the underlining therapeutic mechanisms. Besides, further GPX4 inhibition experiments revealed that MSC-EVs alleviated inflammatory response induced ferroptosis via upregulating GPX4 in vitro. Meanwhile, MSC-EVs could increase the expression of Nrf2 and Nrf2 inhibition alleviated the effects of MSC-EVs. Transwell assay revealed that MSC-EVs could prevent the recruitment and chemotaxis of macrophages induced by ferroptotic hepatocytes. Moreover, we found that there was a significant correlation between levels of circulating 4-HNE and transaminases and treatment response, while overactivation of ferroptosis was revealed in hepatocytes in AIH patients. In conclusion, MSC-EVs could ameliorate inflammatory injury in ILI by suppressing hepatocytes ferroptosis via the Nrf2/GPX4 signaling pathway.