NSUN7 Promotes Pyroptosis of Lung Epithelial Cells in Sepsis-induced Acute Lung Injury by Stabilizing TRAF6

Sepsis-induced acute lung injury (ALI) leads to high mortality. NOP2/Sun RNA methyltransferase family member 7 (NSUN7) is a methyltransferase of 5-methylcytosine (m5C) modification that is highly expressed in sepsis. However, whether NSUN7 affects ALI progression remains largely unknown. This study aimed to investigate the role of NSUN7 in sepsis-induced ALI and its underlying molecular mechanism. A sepsis mouse model was established by cecal ligation puncture, and lung epithelial cells (MLE-12) were exposed to lipopolysaccharide (LPS) to establish an in vitro model. Cell pyroptosis, NSUN7-mediated m5C methylation of tumor necrosis factor receptor-associated factor 6 (TRAF6), and lung pathology and inflammation were analyzed. The results showed that NSUN7 expression was enhanced in the lungs of septic mice and LPS-induced MLE-12 cells. Silencing of NSUN7 suppressed LPS-induced pyroptosis, which was reversed by TRAF6. Additionally, knockdown of NSUN7 decreased TRAF6 expression, reduced TRAF6 m5C levels, and shortened TRAF6 half-life. Moreover, silencing of NSUN7 attenuated lung injury in sepsis mice and decreased proinflammatory factor levels. In conclusion, NSUN7 promotes pyroptosis of lung epithelial cells in sepsis-induced ALI by stabilizing TRAF6 in a m5C-dependent manner. These findings suggest that NSUN7 may be a promising therapeutic target for sepsis-induced ALI.