Sdhd hypermethylation promotes succinate accumulation and NLRP3-related pyroptosis in septic lung injury

Sepsis-induced acute lung injury (Si-ALI) involves metabolic and inflammatory dysregulation; however, its underlying mechanisms remain unclear. Here, we investigated the role of succinate accumulation and epigenetic silencing of succinate dehydrogenase subunit D (SDHD) in Si-ALI using septic mice, macrophages, and a publicly available transcriptomic dataset from patients with sepsis. Succinate supplementation increased lung inflammation, macrophage pyroptosis, and mortality in septic mice. Analysis of the GSE54514 dataset showed reduced SDHD expression in patients with sepsis. In septic mice, Sdhd overexpression reduced succinate accumulation, pyroptosis, lung injury, and mortality. In macrophages, Sdhd overexpression reduced oxidative mitochondrial DNA (ox-mtDNA) release and NLRP3-related pyroptosis. Mechanistically, sepsis-induced upregulation of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) was associated with Sdhd promoter hypermethylation and reduced Sdhd expression. Pharmacological DNMT inhibition with SGI-1027 reversed Sdhd promoter hypermethylation, restored Sdhd expression, reduced succinate accumulation and pyroptosis, and ameliorated lung injury. These findings support a DNMT-SDHD-succinate axis in sepsis-induced lung injury and suggest that targeting this pathway may represent a potential therapeutic target for Si-ALI.