Regulation of renal ischemia-reperfusion injury and tubular epithelial cell ferroptosis by pparγ m6a methylation: mechanisms and therapeutic implications

This study aimed to elucidate the role and underlying mechanisms of Peroxisome proliferator-activated receptor gamma (PPAR gamma) and its m6A methylation in renal ischemia-reperfusion (I/R) injury and ferroptosis of tubular epithelial cells (TECs). High-throughput transcriptome sequencing was performed on renal tissue samples from I/R injury models and sham-operated mice, complemented by in vivo and in vitro experiments focusing on the PPAR gamma activator Rosiglitazone and the manipulation of METTL14 and IGF2BP2 expression. Key evaluations included renal injury assessment, ferroptosis indicator measurement, and m6A methylation analysis of PPAR gamma. Our findings highlight the critical role of the PPAR gamma pathway and ferroptosis in renal I/R injury, with Rosiglitazone ameliorating renal damage and TEC ferroptosis. METTL14-mediated m6A methylation of PPAR gamma, dependent on IGF2BP2, emerged as a pivotal regulator of PPAR gamma expression, renal injury, and ferroptosis. This study reveals that PPAR gamma m6A methylation, orchestrated by METTL14 through an IGF2BP2-dependent mechanism, plays a crucial role in mitigating renal I/R injury and TEC ferroptosis. These insights offer promising avenues for therapeutic strategies targeting acute kidney injury.