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

Area of Science:

• Hepatology and metabolic disease research.
• Biochemistry and enzyme function.
• Genomic stability and DNA repair mechanisms.

Background:

• Tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis is crucial in the liver.
• α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) regulates de novo NAD+ synthesis.
• Boosting NAD+ shows metabolic benefits in mouse models.

Purpose of the Study:

• Investigate ACMSD inhibition for treating metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH).
• Explore ACMSD's role in hepatic NAD+ metabolism and genomic protection.

Main Methods:

• Utilized in vitro models (primary hepatocytes, liver cells, liver organoids) and in vivo mouse models of MASLD/MASH.
• Administered ACMSD inhibitors therapeutically after disease onset in mice.
• Assessed DNA damage responses in human liver organoid models.

Main Results:

• ACMSD inhibition promoted de novo NAD+ synthesis and reduced DNA damage across ex vivo, in vivo, and organoid models.
• MASLD/MASH mouse models showed suppressed de novo NAD+ biosynthesis and DNA damage signatures correlating with severity.
• Therapeutic ACMSD inhibition in mice reversed MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage.

Conclusions:

• ACMSD inhibition enhances hepatic NAD+ levels and provides genomic protection.
• This approach demonstrates therapeutic potential for MASLD/MASH.
• ACMSD is identified as a promising therapeutic target for MASLD/MASH.