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

Abstract

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.