NUPR1 alleviates renal ischemia reperfusion injury by inhibiting ferroptosis involving the ATF4-CHAC1 pathway.

As a major cause of acute kidney injury (AKI), renal ischemia reperfusion injury (IRI) poses a considerable clinical challenge worldwide. Currently, effective therapeutic strategies for renal IRI remain limited. Although ferroptosis has been identified as a pivotal factor in the pathogenesis of renal IRI, the molecular mechanisms underlying the regulation of ferroptosis in renal IRI require further elucidation. To investigate the regulatory role of nuclear protein 1 (NUPR1) in ferroptosis during renal IRI, we established a murine model of renal IRI and an in vitro hypoxia-reoxygenation model using HK2 cells based on bioinformatics analysis. We found that the expression of NUPR1 was markedly upregulated in renal IRI. The overexpression of NUPR1 was found to alleviate renal IRI, whereas injury was exacerbated by an inhibition of NUPR1. Correspondingly, the overexpression of NUPR1 suppressed ferroptosis in renal IRI and HK2 cells exposed to hypoxia-reoxygenation, whereas inhibition or knockdown of NUPR1 enhanced ferroptosis. Furthermore, we detected a significant upregulation of transcription factor 4 (ATF4) in renal IRI and HK2 cells exposed to hypoxia-reoxygenation, and immunoprecipitation revealed an interaction between NUPR1 and ATF4 in HK2 cells. Mechanistically, NUPR1 suppressed ferroptosis by inhibiting the ATF4-CHAC1 pathway. On the basis of our findings in this study, we propose that NUPR1 regulates ferroptosis in renal IRI by modulating the ATF4-CHAC1 pathway, and thus NUPR1 and the ATF4-CHAC1 pathway could serve as promising targets for the treatment of renal IRI.