Mesenchymal Stem Cells Protect Against Ferroptosis via Exosome-Mediated Stabilization of Xct in Acute Liver Injury

Background: Ferroptosis, a newly recognized form of regulated cell death, was recently identified as a novel therapeutic target in tissue injury. Various studies have shown that administration of mesenchymal stem cells (MSC) is a promising therapeutic approach to repair liver injury. However, the role of ferroptosis in acute liver injury (ALI) and MSC-based therapy is unknown. Results: Here we found that CCl4 induced elevated lipid reactive oxygen species (lipid-ROS) and mRNA levels of putative molecular markers of ferroptosis such as Ptgs2 and LOX genes. CCl4 also downregulated the xCT protein levels resulting in the accumulation of lipid peroxidation and ferroptosis. MSC transplantation largely abolished CCl4-induced ferroptosis. Furthermore, the protective effects of MSC against ferroptosis were closely correlated with exosome-mediated stabilization of xCT. Administration of MSC-Exo restored the xCT protein level, decreased the elevated lipid-ROS level and Ptgs2 and LOX mRNA levels, and promoted liver restoration by inhibiting ferroptosis. Interestingly, in ALI mouse livers after MSC-Exo treatment, exosome-induced recovery of xCT protein was accompanied by upregulation of CD44 and OTUB1. The level of ubiquitinated xCT upregulated by CCl4 was significantly downregulated by OTUB1-mediated deubiquitination, and strong interactions of xCT with OTUB1 and CD44 proteins were detected. Conclusions: Taken together, our data indicate that MSC-Exo has a protective role against ferroptosis by maintaining xCT function. This provides a novel therapeutic strategy for ferroptosis-induced ALI.