IL-22 inhibits ferroptosis and attenuates ischemia-reperfusion-induced acute kidney injury: Association with activation of the P62-Keap1-Nrf2 signaling pathway.

Abstract

Acute kidney injury (AKI) remains a major clinical challenge due to its high morbidity and mortality, with ischemia-reperfusion injury (IRI) as one of its primary causes. Severe IRI-associated AKI (IRI-AKI) can progress to irreversible renal failure, yet no effective therapies are currently available. Ferroptosis, an iron-dependent regulated cell death, has recently been implicated in the pathogenesis of IRI-AKI. Moreover, IL-22 may alleviate AKI by modulating the ferroptosis process through regulation of the P62-Keap1-Nrf2 signaling axis. In this study, we examined the protective role of the immune cytokine interleukin-22 (IL-22) in IRI-AKI and its mechanistic association with ferroptosis. Using a murine IRI model and an HK-2 cell hypoxia/reoxygenation system, we systematically assessed the impact of IL-22 treatment. IL-22 administration significantly enhanced renal function, reduced histological injury, and limited both reactive oxygen species accumulation and ferroptotic cell death. Further mechanistic studies demonstrated that IL-22 suppresses ferroptosis in vitro through an Nrf2-dependent mechanism and is associated with activation of the P62-Keap1-Nrf2 signaling pathway. These findings offer experimental evidence supporting IL-22 as a potential therapy for IRI-AKI and highlight ferroptosis modulation as a promising therapeutic strategy.