Metabolic dysfunction-associated steatohepatitis (MASH), driven by insulin resistance, lipid accumulation, and inflammation in the liver, has become the fastest-growing cause of hepatocellular carcinoma. However, effective treatments are still very limited. Until now, only resmetirom and semaglutide have been approved by the Food and Drug Administration of Unites States. There is an urgent need for new therapies that can address the complex metabolic changes behind MASH.

In a study published in Cell Metabolism, a team led by LI Jingya and NAN Fajun from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, DING Yanhua from Jilin University, and the collaborators, discovered that 326E (also known as BGT-002), an enedioic acid analogue they developed, targets both ATP-citrate lyase (ACLY) and peroxisome proliferator-activated receptor alpha (PPARα) to restore hepatic lipid balance and alleviate MASH pathology.

The researchers found that ACLY, a key enzyme in de novo lipogenesis, was highly expressed in MASH patient livers and correlated with disease severity. In rodent and nonhuman primate models, 326E treatment markedly improved steatosis, inflammation, and fibrosis. 

A phase Ib/IIa randomized, double-blind, placebo-controlled trial (NCT06491576) further confirmed its translational potential. Daily oral administration showed good pharmacokinetics (half-life 85-101 hours) and tolerability. After 28 days of treatment, patients exhibited reduced alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GGT), and high-sensitivity C-reactive protein (hs-CRP) levels.

Mechanistic studies showed that intracellular 326E-CoA, formed by ACSVL1-mediated activation specific in liver, competitively bound the CoA pocket of ACLY to inhibit lipid synthesis, and it simultaneously engaged the ligand-binding domain of PPARα through a noncanonical interaction, activating genes involved in fatty acid oxidation and mitochondrial function. This dual-target synergy prevented the compensatory lipogenesis often induced by single PPARα agonists, resulting in coordinated metabolic improvement.

This study identifies BGT-002 (326E) as an ACLY/PPARα dual regulator, offering a potential therapeutic approach for MASH and metabolic liver diseases.