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

Abstract

<h3>Background & Aims</h3> Recent findings reveal the importance of tryptophan-initiated <i>de novo</i> nicotinamide adenine dinucleotide (NAD⁺) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. The enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), primarily expressed in the liver and kidney, acts as a modulator of <i>de novo</i> NAD⁺ synthesis. Boosting NAD⁺ levels has previously demonstrated remarkable metabolic benefits in mouse models. In this study, we aimed to investigate the therapeutic implications of ACMSD inhibition in the treatment of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH). <h3>Methods</h3> <i>In vitro</i> experiments were conducted in primary rodent hepatocytes, Huh7 human liver carcinoma cells and induced pluripotent stem cell-derived human liver organoids (HLOs). C57BL/6J male mice were fed a western-style diet and housed at thermoneutrality to recapitulate key aspects of MASLD/MASH. Pharmacological ACMSD inhibition was given therapeutically, following disease onset. HLO models of steatohepatitis were used to assess the DNA damage responses to ACMSD inhibition in human contexts. <h3>Results</h3> Inhibiting ACMSD with a novel specific pharmacological inhibitor promotes <i>de novo</i> NAD⁺ synthesis and reduces DNA damage <i>ex vivo</i>, <i>in vivo,</i> and in HLO models. In mouse models of MASLD/MASH, <i>de novo</i> 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 inhibition of ACMSD in mice increases liver NAD⁺ and reverses MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage, as observed in HLO models of steatohepatitis. <h3>Conclusions</h3> Our findings highlight the benefits of ACMSD inhibition in enhancing hepatic NAD⁺ levels and enabling genomic protection, underscoring its therapeutic potential in MASLD/MASH. <h3>Impact and implications</h3> Enhancing NAD⁺ levels has been shown to induce remarkable health benefits in mouse models of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH), yet liver-specific NAD⁺ boosting strategies remain underexplored. Here, we present a novel pharmacological approach to enhance <i>de novo</i> synthesis of NAD⁺ in the liver by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), an enzyme highly expressed in the liver. Inhibiting ACMSD increases NAD⁺ levels, enhances mitochondrial respiration, and maintains genomic stability in hepatocytes <i>ex vivo</i> and <i>in vivo</i>. These molecular benefits prevent disease progression in both mouse and human liver organoid models of steatohepatitis. Our preclinical study identifies ACMSD as a promising target for MASLD/MASH management and lays the groundwork for developing ACMSD inhibitors as a clinical treatment.

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