Mitochondrial Double-Stranded RNA Triggers Ferroptosis via PKR-ISR Signaling in Renal Ischemia-Reperfusion Injury

Abstract

Renal ischemia-reperfusion (IR) injury remains a leading cause of acute kidney injury, although the precise molecular pathways responsible for tissue injury are not fully understood. In this study, we demonstrate that IR initiates ferroptosis through activation of the PKR-dependent integrated stress response (ISR), which is driven by the accumulation of mitochondrial double-stranded RNA (dsRNA). Our mechanistic investigations reveal that IR perturbs mitochondrial homeostasis, leading to the accumulation of mitochondrial dsRNA and its subsequent release into the cytosol, thereby activating the dsRNA-dependent kinase PKR. Activation of PKR results in eIF2 phosphorylation and maladaptive ISR signaling, which facilitates ferroptosis and impairs renal function. Notably, genetic ablation of PKR or pharmacological intervention to inhibit ISR significantly reduced ferroptosis and preserved renal function. Collectively, these results identify the mitochondrial dsRNA-PKR-ISR axis as a critical mediator of ferroptotic renal injury and highlight its potential as a therapeutic target in ischemic acute kidney injury.