METTL3 suppresses inflammatory responses by regulating SIRT1-mediated HMGB1 release in sepsis.

Sepsis, a life-threatening systemic inflammation caused by dysregulated host responses to infection, involves complex pathophysiological mechanisms. In eukaryotes, N6-methyladenosine (m6A), a prevalent post-transcriptional RNA modification, is dynamically regulated by "writers" (methyltransferases), "erasers" (demethylases), and "readers" (binding proteins). Although methyltransferase-like 3 (METTL3), a key writer, has been associated with multiple diseases, its role in sepsis remains unclear. This study elucidates how METTL3-mediated m6A modification mitigates sepsis-associated inflammation. Decreased m6A methylation and METTL3 expression levels were seen in peripheral blood mononuclear cells (PBMCs) of sepsis patients and septic animals, as well as in lipopolysaccharide (LPS) activated RAW264.7 cells. Notably, overexpression of METTL3 attenuated inflammatory responses by suppressing HMGB1 secretion. In vivo experiments demonstrated that METTL3 exerted protective effects against sepsis by modulating the SIRT1/HMGB1 axis. Mechanistically, METTL3 inhibited inflammatory response by increasing the stability of SIRT1 mRNA in a YTHDC1-dependent manner to reduce the extracellular release of HMGB1. These findings suggest that METTL3 functions as a crucial regulator of inflammation resolution in sepsis through the SIRT1/HMGB1 pathway, highlighting its potential as a therapeutic target.