Nicotinamide N-oxide alleviates sepsis-induced hepatic inflammation, oxidative stress, and mitochondrial damage depends on SIRT3/AKT signaling pathway

Sepsis frequently gives rise to acute hepatic injury, representing a prevalent and critical pathological manifestation associated with high morbidity and mortality, yet effective therapeutic strategies remain limited. In this study, sepsis-induced acute liver injury was modeled in mice using cecum ligation and puncture (CLP) surgery. The therapeutic potential and underlying mechanisms of Nicotinamide nitrogen oxide (NAMO) were evaluated via intraperitoneal injection at doses of 40, 80, and 160 mg/kg. Histological analysis revealed that increasing doses of NAMO led to more orderly hepatocyte arrangement and significantly reduced vacuolar degeneration and inflammatory cell infiltration. NAMO treatment significantly downregulated the mRNA expression of pro-inflammatory cytokines (iNOS, IL-1β, TNF-α, and IL-6) and upregulated the anti-inflammatory cytokine IL-10. Additionally, NAMO enhanced the activity of antioxidant Enzymes (CAT, GSH, and T-AOC), while reducing levels of lipid peroxidation markers (MDA) and Reactive Oxygen Species (ROS) in both liver tissues and hepatocytes. Furthermore, NAMO restored the protein expression of mitochondrial regulatory factors NRF1 and PGC-1α and preserved intracellular ATP levels, indicating improved mitochondrial function. Mechanistic investigations showed that NAMO exerted its protective effects by modulating mitochondrial homeostasis and oxidative stress through the SIRT3/Akt signaling pathway being blocked. In conclusion, by minimizing oxidative stress and inflammation, keeping mitochondrial integrity, and managing the SIRT3/Akt pathway, NAMO shields with sepsis-induced acute liver injury. The results indicate that NAMO holds significant potential as a therapeutic agent for managing hepatic impairment associated with sepsis.

Inflammation; Liver injury; Mitochondrial damage; Nicotinamide N-oxide; Oxidative stress; Sepsis.