METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome

N6-methyladenosine (m⁶A) RNA modification is a fundamental determinant of mRNA metabolism in eukaryotic cells and is involved in numerous physiological and pathological processes. However, the specific role of m⁶A modification in sepsis-induced acute respiratory distress syndrome(ARDS) remains unknown. Here, we show that the levels of m⁶A RNA were significantly decreased in septic lungs and that METTL3 was the main regulator involved in the absence of m⁶A RNA modification. Pulmonary endothelial barrier damage is a critical process in the pathogenesis of acute lung injury during sepsis. METTL3 regulated endothelial barrier dysfunction and inflammatory responses in sepsis-induced ARDS in vivo and in vitro. Furthermore, we identified tripartite motif-containing (Trim)59 as a key m⁶A effector and Trim59 deficiency exacerbated lung injury. Mechanistically, METTL3 inhibited endothelial injury in sepsis-induced ARDS through Trim59-associated NF-κB inactivation. Our findings revealed novel insights into epitranscriptional mechanisms in sepsis-induced ARDS via m⁶A modifications, which has important application value in the diagnosis, prognosis, and molecular-targeted therapy of sepsis-associated lung injury.