Elevated FTO alleviates sepsis-induced acute kidney injury by regulating macrophage inflammatory phenotypes [MeRIP-seq]

Recent 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. In this study, we analyzed the dataset GSE32707 and GSE69063, fat mass and obesity-associated protein (FTO) was identified as the sole gene exhibiting significant downregulation within the transcriptome of peripheral blood samples from sepsis patients among m6A-related proteins. We further demonstrated that septic mice subjected to cecal ligation and puncture (CLP) presented increased m6A modifications and reduced FTO expression in both renal tissues and peritoneal macrophages (PMs). Our findings revealed that increased levels of FTO correlated with reduced mortality and kidney damage during sepsis and that the upregulation of FTO in lipopolysaccharide (LPS)-stimulated macrophages led to decreased production of proinflammatory cytokines. Mechanistically, through multiomic analysis of macrophages, we identified a novel mechanism involving matrix metalloproteinase 9 (MMP-9) as a direct target of FTO, which positively affects its translation efficacy. Furthermore, both in vivo and in vitro data confirmed that reduced MMP-9 levels exerted adverse effects on mitigating inflammatory responses and alleviating renal injury. Overall, our findings underscore the critical role of the FTO/m6A/MMP-9 axis in the regulation of proinflammatory secretion and improve our understanding of the transcriptomic landscape during the progression of SAKI.