2. Academic Validation
  3. A potential therapeutic effect of 84-B10 in MASLD through promotion of FASN degradation

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

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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