ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH. ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH

Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress. Overall design: To investigate the effect of ACMSD inhibition, mouse primary hepatocytes were treated with ACMSD inhibitor TLC-065 for 6, 12, and 24h. The effects of TLC-065 were tested in human liver organoid models of steatohepatitis.