NMN mitigates LPS-induced liver injury by inhibiting ferroptosis via suppression of the cGAS-STING-ACSL4 axis.

Sepsis often leads to severe liver damage, and currently few effective therapies are available for it. Nicotinamide mononucleotide (NMN), a well-known anti-aging agent, exerts organ-protective effects, yet its detailed mechanisms against acute liver injury remain poorly understood. Here, we established LPS-induced liver injury mouse models, along with in vitro models using primary hepatocytes, primary macrophages and THP-1 cells. We found that LPS triggers ferroptosis and inflammation in both macrophages and hepatocytes, and paracrine inflammatory signals from macrophages further aggravate hepatocyte ferroptosis. NMN effectively reverses these pathological changes. Mechanistically, NMN suppressed mtDNA-mediated cGAS-STING activation and weakened the interaction between STING and ACSL4. Domain mapping, molecular simulations, surface plasmon resonance (SPR) analysis, co-immunoprecipitation and hepatic proximity ligation assay (PLA) collectively demonstrated that NMN destabilized the STING-ACSL4 complex, thereby restraining ferroptosis. In conclusion, NMN protects against LPS-induced acute liver injury by concurrently suppressing cGAS-STING-mediated inflammation and weakening the pro-ferroptotic STING-ACSL4 interaction.