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

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.