Inhibitors of p53 Apoptosis-Stimulating Protein Mitigate Acute Kidney Injury by Modulating the HIF-1α/SLC7A11 Pathway to Suppress Ferroptosis

Acute kidney injury (AKI) is a complex disease caused by different causes, especially ischaemia-reperfusion (I/R) injury. Ferroptosis is the main form of I/R-induced organ injury, and blocking Ferroptosis has demonstrated therapeutic potential in ameliorating organ injury. We investigated the roles of apoptosis-stimulating protein of p53 (iASPP) and hypoxia-inducible factor-1α (HIF-1α) in Ferroptosis during renal I/R injury. HIF-1α gene was knocked out in a hypoxia/reoxygenation model of renal tubular epithelial cells, and iASPP overexpression and knockdown plasmids were transfected. In I/R mouse models, conditional knockout of HIF-1α mice and injection of overexpressed iASPP adeno-associated viruses were used to validate downstream ferroptosis-related changes. The results showed that the Ferroptosis level of mice in the I/R group was increased, and the addition of Ferrostatin-1 (Fer-1) and FG-4592 could alleviate the Ferroptosis. HIF-1α conditional knockout mice showed exacerbated Ferroptosis. HIF-1α can directly interact with SLC7A11, a key Ferroptosis regulator, modulating Ferroptosis progression. Similar to HIF-1α, iASPP expression was significantly increased in the I/R group, and overexpression of iASPP upregulated HIF-1α and SLC7A11 expression, consequently mitigating ferroptosis-mediated damage. In summary, our study suggests that iASPP exerts renal protection during I/R injury by regulating the HIF-1α/SLC7A11 axis to suppress Ferroptosis.

AKI; ferroptosis; hypoxia‐inducible factor 1α; iASPP; ischaemia–reperfusion.