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 a-amino-ß-carboxymuconate-e-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: The therapeutic effect of TLC-065 was evaluated in a dietary mouse model of MASLD/MASH, where treatment commenced nine weeks after initiating a Western diet feeding regimen for 14 weeks. The same part of liver were collect from each mouse, snap freezed in liquid nitrogen and stored in -80 for mRNA extraction, purification and RNAseq.