RNA-binding protein STAT3 regulates GSDME mRNA homeostasis to mediate pyroptosis in Renal Ischemia-Reperfusion Injury

Acute kidney injury (AKI) is a critical global health issue, characterized by sudden renal dysfunction often triggered by ischemia-reperfusion injury (IRI). The pathogenesis involves oxidative stress, inflammation, and cell death pathways, yet the role of RNA-binding proteins (RBPs) in this process remains underexplored. This study employed single-cell RNA sequencing (scRNA-seq) and bioinformatics analyses to investigate RBP expression in proximal tubular cells (PTCs) during AKI progression. Through in vivo and in vitro models, we identified STAT3 as a pivotal regulator exacerbating renal injury by enhancing GSDME mRNA stability, thereby promoting pyroptosis. Conditional knockout of STAT3 in renal tubular cells alleviated pyroptosis and inflammation in IRI models, demonstrating significant reductions in inflammatory cytokine levels and improved renal function. This research underscores STAT3's dual role as a transcription factor and RBP, linking its RNA-binding capability to pyroptosis regulation. These findings provide novel insights into AKI pathophysiology and highlight STAT3 as a potential therapeutic target.