Mesenchymal Stem Cells Prevent SLC39A14‐Dependent Hepatocyte Ferroptosis through Exosomal miR‐16‐5p in Liver Graft

Abstract Ischemia‐reperfusion injury (IRI) is the leading cause of hepatic graft dysfunction, resulting from hepatocyte damage. Nevertheless, given the few specialized therapeutics available in hepatic IRI, additional mechanistic insights into hepatocyte damage are required. Here, the protein solute carrier family 39 member 14 (SLC39A14) is identified as a pro‐ferroptosis target in hepatocytes of human liver allografts through single‐cell RNA sequencing analysis. SLC39A14 knockdown significantly mitigated hepatic IRI by preventing hepatocyte ferroptosis in vivo and in vitro. Mechanistically, the inhibition of SLC39A14 suppressed non‐transferrin‐bound iron (NTBI) uptake by hepatocytes, thereby reducing iron overload and cell ferroptosis. Moreover, human bone marrow‐derived mesenchymal stem cells (hBMSCs) are found to exhibit a notable therapeutic effect on hepatic IRI by downregulating SLC39A14 expression. Exosomes derived from hBMSCs delivered abundant miR‐16‐5p into hepatocytes, which post‐transcriptionally suppressed the expression of SLC39A14 and reduced cell ferroptosis induced by hepatic IRI. In conclusion, SLC39A14 triggers hepatic IRI by mediating NTBI uptake into hepatocytes and inducing hepatocyte ferroptosis. Moreover, hBMSC‐based therapy is promising to reverse this progression of hepatic IRI.