2025年10月22日出版的《细胞—代谢》杂志发表了中国科学家的一项最新研究成果。来自中国科学院上海药物研究所的李静雅小组揭示了内酯酸类似物326E通过双重靶向ACLY和PPARα减轻代谢功能障碍相关的脂肪性肝炎。

代谢功能障碍相关脂肪性肝炎（MASH）患病率的上升主要归因于脂质代谢失调。本研究发现，高胆固醇血症2a期临床研究新药烯二酸ATP-柠檬酸裂解酶（ACLY）抑制剂326E在无主题模型中显著降低肝脏脂质积累，缓解MASH。机制研究表明，326E不仅通过抑制ACLY减少新生脂肪生成（DNL）发挥这些作用，而且还作为过氧化物酶体增殖物激活受体α (PPARα)变抗调节剂增加肝脏脂肪酸氧化（FAO）。激活的PPARα对MASH的功效通过抑制FAO产品的再循环来提高脂质积累，这是ACLY抑制的结果。随后对猕猴（Macaca fascicularis）的研究证实了326E对灵长类动物MASH的有效性。在一项针对MASH患者（NCT06491576）的随机1b/2a期临床试验中，326E耐受性良好，可降低循环γ-谷氨酰转移酶（γ-GGT）。综上所述，他们的结果表明326E通过抑制ACLY和激活PPARα的独特双重机制对MASH的治疗潜力。

附：英文原文

Title: The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα

Author: Zhifu Xie, Long Cheng, Yue Hu, Gaolei Song, Fan Wang, Mei Zhang, Yangming Zhang, Xinwen Zhang, Chendong Zhou, Xiaoxue Zhu, Xinyu Sun, Honghong Xu, Qian Song, Yulin Yang, Jie Zheng, Shaohui Ji, Jiming Ye, Chen Zhou, Xiaoying Lai, Wei Li, Yifan Zhang, Xiaoyan Chen, Junqi Niu, Yanhua Ding, Fajun Nan, Jingya Li

Issue&Volume: 2025-10-22

Abstract: The rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. This study discovered that the enedioic acid ATP-citrate lyase (ACLY) inhibitor 326E, an investigational new drug in a phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ACLY to reduce de novo lipogenesis (DNL) but also as a peroxisome proliferator-activated receptor α (PPARα) allosteric regulator to increase hepatic fatty acid oxidation (FAO). The efficacy of activated PPARα for MASH is enhanced by suppressed recycling of FAO products to lipid accumulation as a result of ACLY inhibition. Subsequent studies in cynomolgus monkeys (Macaca fascicularis) confirmed the effectiveness of 326E for MASH in primate species. In a randomized phase 1b/2a clinical trial in patients with MASH (NCT06491576), 326E was well tolerated and reduced circulating gamma-glutamyl transferase (γ-GGT). Taken together, our results indicate the therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPARα.

DOI: 10.1016/j.cmet.2025.09.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00396-1