The monoacylglycerol acyltransferase 2 inhibitor VB-85387 reduces MASLD.

Metabolic dysfunction-associated liver disease (MASLD) arises from the accumulation of triglycerides within the liver. MASLD can advance to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. Monoacylglycerol acyltransferase 2 (MOGAT2) is essential for triglyceride synthesis and plays a significant role in regulating lipid metabolism. Here, we demonstrate the ability of a new human MOGAT 2 inhibitor, VB-85387, to inhibit the development of MASLD/MASH and further define its effects on the key metabolic pathways that progress MASH development. MASLD/MASH was induced using a methionine, choline-deficient diet (LMCD) or by streptozotocin treatment combined with high fat diet feeding (STAM-HFD). VB-85387 significantly mitigated the severity of MASLD and reduced signs of MASH in mice subjected to these two distinct diets. VB-85387-treated mice exhibited decreased fibrosis, evidenced by reduced hepatic triglyceride concentrations, hydroxyproline levels, and collagen deposition. NAS scores were consistently lower in VB-85387-treated mice across both models. VB-85387-treated mice showed induced PPARα signaling and reduced SREBP transcription, demonstrating a likely role for VB-85387 in regulating lipogenesis and fatty acid β-oxidation. STAM-HFD treated mice showed lower NF-κBp65 activation, which was associated with lower TNFα expression. IL-1β and IFNβ levels were also both reduced, suggesting VB-85387 can reduce pro-inflammatory pattern recognition receptor signaling. In addition, treatment suppressed IL-4/IL-6-dependent JAK activation. Overall, VB-85387 inhibited MASLD development by reducing liver triglyceride levels, fibrosis, and meta-inflammatory signaling. VB-85387 was as effective or superior to the MOGAT2 inhibitor phase I clinical trial drug BMS-963272 in reducing MASLD and fibrosis. VB-85387 has considerable potential for developing therapeutics targeting MASLD/MASH.