Protective Effect of Hepcidin on Sepsis-Associated Acute Kid-ney Injury via Activating the Nrf2/GPX4 Signaling Pathway

Background: Hepcidin not only sustains systemic iron homeostasis but also functions as an antimicrobial peptide. During this study, we sought to analyze the ability of hepcidin to protect against sepsis-associated acute kidney injury (SAKI) and elucidated its un-derlying mechanisms in mediating ferroptotic pathways. Methods: A SAKI mouse model was created via cecal ligation and puncture (CLP), along with an LPS-induced Human Kidney-2 (HK-2) cell model, to study the protective mechanism of Hepcidin against SAKI. Through the analysis of renal injury biomarkers and ferroptosis-related molecules, combined with quantitative detection of nuclear factor-erythroid 2-related factor-2 (Nrf2) nuclear translocation and glutathione peroxi-dase 4 (GPX4), a regulatory protein of ferroptosis, we uncovered the hepcidin-mediated mechanisms underlying ferroptosis in septic kidney injury. Results: Hepcidin improved survival rates in SAKI mice and concurrently reduced SCr and BUN levels. It also reduced the production of IL-6, IL-1β, and TNF-α, and decreased renal injury markers. By upregulating GPX4 expression and increasing GSH levels, hepcidin exerts a protective effect against renal oxidative stress. Additional investiga-tions reveal that hepcidin promotes nuclear Nrf2 expression, with this upregulation mediating downstream GPX4 to suppress renal ferroptosis which is caused by sepsis. Conclusions: Protective effects of hepcidin against SAKI are mediated by the Nrf2/GPX4 ferroptosis pathway, underscoring its therapeutic potential for SAKI.