Acute Kidney Injury Remodels Hepatic Iron Handling and Depletes Glutathione Defense in the Mouse Liver

Objective Acute kidney injury damages the liver; its redox state is undescribed. We asked whether the liver's defensive response to a distant renal insult coincides with loss of its antioxidant defense. Methods Male C57BL/6J mice underwent 30 min bilateral renal ischemia and 24 h reperfusion. Hepatic RNA sequencing and proteomics from the same animals were integrated by sparse multiblock discriminant analysis and the predictions tested by iron, glutathione, and lipid peroxidation assays and in HepG2 cells. Results Integration selected an interleukin‐6/STAT3 acute‐phase axis. The transcriptional iron program favored uptake and blocked export (transferrin receptor 1 and hepcidin induced, ferroportin repressed, ferritin unchanged), while tissue iron moved the other way: total non‐heme iron fell by a quarter and ferrous‐reactive iron did not differ, so the liver was not iron loaded. Glutamate‐cysteine ligase subunits and GTP cyclohydrolase 1 fell, inferred NRF2 activity was repressed, and the glutathione redox couple collapsed 8.4‐fold; glutathione peroxidase 4 was unchanged and the ferroptosis gene set was not enriched, yet lipid peroxidation proceeded. Plasma from donors with acute kidney injury depleted glutathione, raised malondialdehyde, and killed HepG2 cells; ferrostatin‐1 and deferoxamine each attenuated all three. Conclusions Without a cell death readout or rescue in vivo, we report coincident loss of glutathione defense and remodeled iron handling rather than ferroptotic death. The significance is the match between the two arms: the donor plasma killed human liver cells by a route an iron chelator and a radical‐trapping antioxidant each blocked, the chemistry the depleted hepatic glutathione system exists to contain.