最近的研究结果揭示了肝脏中色氨酸引发的烟酰胺腺嘌呤二核苷酸（NAD）从头合成的重要性，这一过程以前被认为是烟酰胺生物合成的继发过程。 α-氨基-β-羧基粘康酸-ε-半醛脱羧酶 (ACMSD) 主要在肝脏和肾脏中表达，充当 NAD 从头合成的调节剂。此前，提高 NAD 水平已在小鼠模型中证明了显着的代谢益处。在本研究中，我们旨在探讨ACMSD抑制在治疗代谢功能障碍相关的脂肪性肝病/脂肪性肝炎（MASLD/MASH）中的治疗意义。在原代啮齿动物肝细胞、Huh7人肝癌细胞和iPSC中进行了体外实验-衍生的人类肝脏类器官（HLO）。 C57BL/6J 雄性小鼠采用西式饮食喂养并饲养在热中性环境中，以概括 MASLD/MASH 的关键方面。疾病发作后，进行药理学 ACMSD 抑制治疗。脂肪性肝炎 HLO 模型用于评估人类环境中 ACMSD 抑制引起的 DNA 损伤反应。用新型特异性药理学抑制剂抑制 ACMSD 可促进 NAD 从头合成，并减少离体、体内和 HLO 模型中的 DNA 损伤。在 MASLD/MASH 小鼠模型中，NAD 从头生物合成受到抑制，转录组 DNA 损伤特征与疾病严重程度相关；在人类中，基于孟德尔随机化的遗传分析表明基因组应激对肝病易感性有显着影响。正如在脂肪性肝炎的 HLO 模型中观察到的那样，对小鼠 ACMSD 进行治疗性抑制可增加肝脏 NAD 并逆转 MASLD/MASH，从而减轻纤维化、炎症和 DNA 损伤。我们的研究结果强调了 ACMSD 抑制在增强肝脏 NAD 水平和实现基因组保护方面的益处，强调了其在 MASLD/MASH 中的治疗潜力。提高 NAD 水平在 MASLD/MASH 小鼠模型中显示出显着的健康益处，但肝脏特异性 NAD 增强策略仍未得到充分探索。在这里，我们提出了一种新的药理学方法，通过抑制 ACMSD（一种在肝脏中高表达的酶）来增强肝脏 NAD 从头合成。抑制 ACMSD 会增加 NAD 水平，增强线粒体呼吸，并维持离体和体内肝细胞的基因组稳定性。这些分子益处可防止小鼠和人类肝脏类器官脂肪性肝炎模型的疾病进展。我们的临床前研究将 ACMSD 确定为 MASLD/MASH 管理的一个有希望的目标，并为开发 ACMSD 抑制剂作为临床治疗奠定了基础。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

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. The enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), primarily expressed in liver and kidney, acts as a modulator of de novo 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).In vitro experiments were conducted in primary rodent hepatocytes, Huh7 human liver carcinoma cells and iPSC-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. Steatohepatitis HLO models were used to assess the DNA damage responses by ACMSD inhibition in human contexts.Inhibiting ACMSD with a novel specific pharmacological inhibitor promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo, and in 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 inhibition of ACMSD in mice increases liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage, as were observed in HLO models of steatohepatitis.Our findings highlight the benefits of ACMSD inhibition to enhance hepatic NAD+ levels and enable genomic protection, underscoring its therapeutic potential in MASLD/MASH.Enhancing NAD+ levels has shown remarkable health benefits in mouse models of MASLD/MASH, yet liver-specific NAD+ boosting strategies remain underexplored. Here, we present a novel pharmacological approach to enhance liver NAD+de novo synthesis by inhibiting ACMSD, an enzyme highly expressed in the liver. Inhibiting ACMSD increases NAD+ levels, enhances mitochondrial respiration, and maintains genomic stability in hepatocytes ex vivo and in vivo. 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.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.