METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

Abstract

Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis‐induced acute lung injury (SI‐ALI). We demonstrate that NETs induce SI‐ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI‐ALI is accompanied by upregulation of ferroptosis depending on METTL3‐induced m6A modification of hypoxia‐inducible factor‐1α (HIF‐1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI‐ALI caused by NETs in a caecum ligation and puncture (CLP)‐induced SI‐ALI model using METTL3 condition knockout (CKO) mice and wild‐type mice. Our results indicate the crucial role of NETs in the progression of SI‐ALI via NET‐activated METTL3 m6A‐IGF2BP2‐dependent m6A modification of HIF‐1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.

Abstract

Highlights

• NETs induce ferroptosis in alveolar epithelial cells via activation of METTL3‐mediated m6A modification.

• METTL3 induces HIF‐1α upregulation via m6A‐IGF2BP2‐dependent mechanism to exacerbate ferroptosis.

• METTL3 induces enhanced glycolysis and decreased oxidative phosphorylation in alveolar epithelial cells.

• Inhibiting NET formation via peptidyl arginine deiminase 4 knockout attenuates ferroptosis and sepsis‐associated lung damage in mice.