A potential therapeutic effect of 84-B10 in MASLD through promotion of FASN degradation

  • Acta Pharmacol Sin. 2026 Jul;47(7):1840-1855. doi: 10.1038/s41401-025-01745-x.
Yi-Peng Bai  #  1  2  3 ,  Yin Yin  #  1 ,  Su-Man Wang  #  2  3 ,  Jiang-Ming Chen  1 ,  Ze-Hua Zhang  1  2  3 ,  Zi-Qi Zhu  2  3  4 ,  Guang-Xin Shao  1  2  3 ,  Yong Zhu  1  2  3 ,  Yi-Yang Jiang  5  6  7 ,  Bei-Cheng Sun  8  9  10 ,  Deng-Qiu Xu  11  12  13  14
Affiliations
  • 1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.
  • 2. MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, 230032, China.
  • 3. Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, 230032, China.
  • 4. School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
  • 5. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China. [email protected].
  • 6. MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, 230032, China. [email protected].
  • 7. Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, 230032, China. [email protected].
  • 8. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China. [email protected].
  • 9. MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, 230032, China. [email protected].
  • 10. Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, 230032, China. [email protected].
  • 11. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China. [email protected].
  • 12. MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, 230032, China. [email protected].
  • 13. Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, 230032, China. [email protected].
  • 14. School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. [email protected].
  • # Contributed equally.
PMID: 41760780 DOI: 10.1038/s41401-025-01745-x
Abstract

Recent evidence shows that fatty acid synthase (FASN), a key regulator of de novo lipogenesis (DNL), is a promising therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD). FASN inhibitors are under advanced clinical trials. In this study, we evaluated the therapeutic efficacy of a novel FASN inhibitor 84-B10 for the treatment of MASLD. RNA-seq analysis showed that FASN was significantly upregulated in PA/OA-treated mouse primary hepatocytes. In silico molecular docking screening combined with biochemical assay, 84-B10 exhibited the strongest FASN-inhibiting effect. We demonstrated that 84-B10 directly bound to the MAT domain of FASN, inhibiting its enzymatic activity and promoting its ubiquitination and proteasomal degradation. In mouse primary hepatocytes, 84-B10 induced Lys48-linked ubiquitination of FASN by recruiting the E3 Ligase tripartite motif-containing 28 (TRIM28), leading to FASN protein degradation. In PA/OA-treated mouse primary hepatocytes, 84-B10 (5, 10 μM) dose-dependently ameliorated lipid accumulation and mitochondrial dysfunction. In HFD-fed mice, administration of 84-B10 (5 mg/kg, i.g. every Other day for 6 weeks) significantly alleviated metabolic alterations and hepatic lipid accumulation. Our results establish 84-B10 as a novel FASN inhibitor that activating the FASN-TRIM28 axis by binding to the MAT domain, facilitating the proteasomal degradation of FASN. With favorable safety, tolerability, and pharmacokinetic properties, 84-B10 holds promise as a therapeutic candidate for the prevention and treatment of MASLD.

Keywords
84-B10; FASN inhibitor; MASLD; TRIM28; lipid metabolism; proteasomal degradation.
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