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

Area of Science:

• Nephrology
• Cellular Biology
• Molecular Medicine

Background:

• Acute kidney injury (AKI) is a significant clinical challenge, often exacerbated by ischemia-reperfusion (I/R) injury.
• Ferroptosis, a regulated form of cell death, plays a critical role in I/R-induced organ damage, presenting a therapeutic target.
• The interplay between hypoxia-inducible factor-1α (HIF-1α) and apoptosis-stimulating protein of p53 (iASPP) in renal ferroptosis remains incompletely understood.

Purpose of the Study:

• To investigate the roles of iASPP and HIF-1α in ferroptosis during renal I/R injury.
• To elucidate the molecular mechanisms by which iASPP influences ferroptosis and renal protection.
• To explore the potential of targeting the iASPP/HIF-1α/SLC7A11 axis for AKI treatment.

Main Methods:

• Utilized hypoxia/reoxygenation models of renal tubular epithelial cells with HIF-1α knockout and iASPP manipulation.
• Employed renal I/R mouse models, including conditional HIF-1α knockout mice and adeno-associated virus-mediated iASPP overexpression.
• Assessed ferroptosis levels and analyzed the interaction between HIF-1α and SLC7A11, a key ferroptosis regulator.

Main Results:

• Renal I/R injury significantly increased ferroptosis, which was alleviated by ferroptosis inhibitors Ferrostatin-1 and FG-4592.
• HIF-1α conditional knockout exacerbated ferroptosis, while HIF-1α directly interacted with and modulated SLC7A11.
• iASPP expression increased in I/R injury; its overexpression upregulated HIF-1α and SLC7A11, mitigating ferroptosis-induced damage.

Conclusions:

• iASPP confers renal protection in I/R injury by suppressing ferroptosis.
• The protective effect of iASPP is mediated through the regulation of the HIF-1α/SLC7A11 axis.
• Targeting the iASPP/HIF-1α/SLC7A11 pathway represents a promising therapeutic strategy for AKI.