Elevated FTO alleviates sepsis‑induced acute kidney injury by regulating macrophage inflammatory phenotypes

Studies have linked the dysregulation of N6‑methyladenosine (m6A) to sepsis‑induced acute kidney injury (SAKI), highlighting the persistent challenge of managing excessive proinflammatory cytokine production and subsequent organ dysfunction. The present study, by analyzing the GSE32707 and GSE69063 datasets, found that fat mass and obesity‑associated protein (FTO) was the sole m6A‑related gene markedly downregulated in the peripheral blood transcriptome of patients with sepsis. It further demonstrated that septic mice subjected to cecal ligation and puncture presented increased m⁶A modifications and reduced FTO expression in both renal tissues and peritoneal macrophages. The findings revealed that increased levels of FTO was associated with reduced mortality and kidney damage during sepsis and that the upregulation of FTO in lipopolysaccharide‑stimulated macrophages led to decreased production of proinflammatory cytokines. Mechanistically, through multiomic analysis of macrophages, the present study identified a novel mechanism involving matrix metalloproteinase 9 (MMP‑9) as a direct target of FTO, which positively affects its translation efficacy. Furthermore, both <i>in vivo</i> and <i>in vitro</i> data confirmed that reduced MMP‑9 levels exerted adverse effects on mitigating inflammatory responses and alleviating renal injury. Overall, the findings underscored the critical role of the FTO/m⁶A/MMP‑9 axis in the regulation of proinflammatory secretion and improved our understanding of the transcriptomic landscape during the progression of SAKI, suggesting that targeting the FTO/m⁶A/MMP‑9 axis may offer therapeutic potential for mitigating renal injury in septic patients.