Proteomics And Metabolomics Reveal The Mechanisms Of NAD~+ Precursors In Inhibiting Liver Fibrosis

Liver fibrosis is a reversible wound-healing response to acute or chronic liver injury that can progress to cirrhosis and hepatocellular carcinoma.Finding new approaches for prevention and management of liver fibrosis is urgently needed.Recent studies have suggested enhancing nicotinamide adenine dinucleotide（NAD⁺）levels by supplementing nicotinamide mononucleotide（NMN）or nicotinamide（NAM）improves multiple organ functions,including liver functions,which providing us a potential strategy for the treatment of liver fibrosis.It is known that hepatic stellate cell（HSC）is the primary source of extracellular matrix that drives liver fibrosis progression.Herein,we carried out a comprehensive secretome profiling to identify NMN-induced changes in secretory proteins and found that NMN suppressed the secretion of profibrotic proteins and oxidoreductases in activated HSC cells.Real-time quantitative PCR analysis revealed that NMN downregulated profibrotic gene expression,resulting in HSC inactivation.Furthermore,we determined that NMN inhibited oxidation-mediated 15-PGDH degradation to promote prostaglandin E₂ degradation and suppress HSC activation.On the other hand,comprehensive secretome profiling revealed that NAM also suppressed the secretion of profibrotic proteins.We also demonstrated that nicotinamide mononucleotide reduced the accumulation of liver extracellular matrix and alleviated liver injury in thioacetamide（TAA）and carbon tetrachloride（CCl₄）induced mouse models for liver fibrosis.NAM alleviated liver fibrosis,but not liver injury.Moreover,we provided comprehensive metabolome resources to investigate the mechanisms under our finding and the results suggested NMN supplementation improved liver injury through increasing the levels of NAD⁺and glutathione（GSH）in mouse liver.In summary,our results propose that NMN supplementation is a new therapeutic approach for liver fibrosis.