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 underlying 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 peroxidase 4 (GPX4), a regulatory protein of ferroptosis, we uncovered the hepcidin-mediated mechanisms underlying ferroptosis in SAKI. Results: Hepcidin significantly attenuated renal function impairment in mice with SAKI and reduced the sepsis-driven increase in inflammatory mediators. As sepsis was associated with enhanced renal ferroptosis, hepcidin exerted a therapeutic effect by mitigating ferroptosis to a degree comparable with that of the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Furthermore, hepcidin conferred renoprotective effects in SAKI by promoting the nuclear translocation of Nrf2, which in turn mediated the upregulation of the downstream anti-ferroptotic protein GPX4. Importantly, the Nrf2 inhibitor ML385 abrogated both the hepcidin-induced nuclear translocation of Nrf2 and the subsequent increase in GPX4 expression. Conclusions: Protective effects of hepcidin against SAKI are mediated by the Nrf2/GPX4 ferroptosis pathway, underscoring its therapeutic potential for SAKI.
Guo et al. (Thu,) studied this question.