Human umbilical cord-derived mesenchymal stem cells attenuate liver fibrosis by inhibiting hepatocyte ferroptosis through mitochondrial transfer

Liver fibrosis is a reversible dynamic pathological process induced by chronic liver injury. Without intervention, liver fibrosis can progress to become cirrhosis, liver failure, or hepatocellular carcinoma, thus posing a high global health burden. Therefore, effective therapies for liver fibrosis are urgently required. Although transplantation of mesenchymal stem cells (MSCs) has significant value as a treatment strategy for liver damage, the underlying mechanisms remain unclear. Chronic liver injury progression is significantly influenced by hepatocyte ferroptosis, and targeting ferroptosis is emerging as a potential treatment strategy for liver fibrosis. Here, we showed that the infusion of human umbilical cord-derived MSCs (hUC-MSCs) alleviated TAA-induced liver fibrosis, improved liver functionality, and decreased ferroptosis in mice. hUC-MSCs inhibit ferroptosis-related mitochondrial damage and lipid peroxidation in AML12 cells in vitro. Mechanistically, under oxidative stress, hUC-MSCs transfer healthy mitochondria to damaged hepatocytes through tunneling nanotubes (TNTs). Cytochalasin D (CytoD), an inhibitor of TNT formation, abrogated the protective effects of hUC-MSCs against ferroptosis. This research emphasizes the ability of hUC-MSCs to serve as a promising treatment for liver fibrosis via mitochondrial transfer through TNTs.