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

  • Cell Metab. 2025 Oct 22:S1550-4131(25)00396-1. doi: 10.1016/j.cmet.2025.09.011.
Zhifu Xie  1 ,  Long Cheng  1 ,  Yue Hu  2 ,  Gaolei Song  3 ,  Fan Wang  4 ,  Mei Zhang  3 ,  Yangming Zhang  5 ,  Xinwen Zhang  3 ,  Chendong Zhou  3 ,  Xiaoxue Zhu  2 ,  Xinyu Sun  3 ,  Honghong Xu  3 ,  Qian Song  3 ,  Yulin Yang  1 ,  Jie Zheng  3 ,  Shaohui Ji  6 ,  Jiming Ye  7 ,  Chen Zhou  3 ,  Xiaoying Lai  8 ,  Wei Li  8 ,  Yifan Zhang  3 ,  Xiaoyan Chen  3 ,  Junqi Niu  2 ,  Yanhua Ding  9 ,  Fajun Nan  10 ,  Jingya Li  11
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
  • 2. Phase I Clinical Research Center, First Hospital of Jilin University, Changchun 130021, P.R. China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
  • 4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; Burgeon Therapeutics Co., Ltd, Shanghai 201203, P.R. China.
  • 6. Kunming Biomed International, Kunming 650500, P.R. China.
  • 7. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; Kunming Biomed International, Kunming 650500, P.R. China.
  • 8. Burgeon Therapeutics Co., Ltd, Shanghai 201203, P.R. China.
  • 9. Phase I Clinical Research Center, First Hospital of Jilin University, Changchun 130021, P.R. China. Electronic address: [email protected].
  • 10. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, P.R. China. Electronic address: [email protected].
  • 11. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, P.R. China. Electronic address: [email protected].
PMID: 41130202 DOI: 10.1016/j.cmet.2025.09.011
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.

Keywords
326E; ACLY; PPARα; fatty acid β-oxidation; lipogenesis; metabolic dysfunction-associated steatohepatitis; phase 1b/2a clinical trial.
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