Dysbiotic Microbiota-Induced Ammonium Stress Drives Intestinal Barrier Dysfunction and MASH Progression: The Therapeutic Promise of DT-109
Ontology highlight
ABSTRACT:
ORGANISM(S): Macaca fascicularis
PROVIDER: GSE279424 | GEO | 2026/03/30
REPOSITORIES: GEO
Dataset's files
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Project description: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 PPARα 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 PPARα.
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