The enedioic acid analogue 326E alleviates MASH in preclinical studies and its signatures in patients via dual targeting at ACLY and PPARa [RNA-Seq]

The alarming rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. The present study discovered that a novel enedioic acid ACLY inhibitor 326E, an investigational new drug in Phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in two different mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ATP-citrate lyase (ACLY) to reduce de novo lipogenesis but also as a PPARa agonist to increase hepatic fatty acid oxidation with promoted mitochondrial biogenesis. 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 MASH patients 326E was well tolerated and demonstrated a therapeutic potential for MASH signatures. Our results reveal a promising therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPARa. Overall design: To elucidate possible mechanisms responsible for 326E's effect in ameliorating MASH, we conducted RNA-seq in the liver samples of CDAA-HFD fed mice after 6 weeks of treatment with 30 mg/kg 326E.