Nicotinamide N-oxide alleviates sepsis-induced acute lung injury by inhibiting ferroptosis through activation of the SIRT1/AKT signalling pathway.

Sepsis is a severe systemic inflammatory response in which the lungs are often the first organ affected. Given the known inhibitory effects of nicotinamide N-oxide (NAMO) on inflammatory cell activation, this study sought to assess its protective function in a mouse model of acute lung damage generated by sepsis. The caecal ligation and puncture (CLP) technique was employed to induce sepsis, and 40, 80, and 160 mg/kg NAMO were given intraperitoneally. In a dose-dependent manner, NAMO dramatically reduced inflammatory cell infiltration, interstitial lung oedema, neutrophil aggregation, and macrophage activation. In lung tissues and cells, NAMO therapy decreased lipid peroxidation (MDA), increased the activities of antioxidant enzymes (CAT, GSH-Px, and T-AOC), and decreased the mRNA expression levels of proinflammatory cytokines. Western blot analysis revealed that NAMO modulates the protein levels of GPX4 and SLC7A11, thereby reducing cell death, Fe2+ accumulation, and ROS levels. Mechanistically, silencing SIRT1 attenuated NAMO-induced activation of the AKT signalling pathway, indicating that SIRT1 is required for NAMO-mediated AKT activation. Moreover, NAMO effectively mitigated sepsis-induced ferroptosis by modulating iron metabolism-related markers through the SIRT1/AKT signalling pathway. In conclusion, NAMO inhibits ferroptosis and alleviates sepsis-induced acute lung injury by activating the SIRT1-mediated AKT signalling pathway.