Pharmacological GPR39 activation protects against MASLD/MASH and improves metabolic syndrome features: a preclinical study in diet-induced mouse models

Effective therapeutics for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed as their global prevalence continues to rise. Deficiency of the G-protein-coupled receptor GPR39 predisposes to obesity and hepatosteatosis, yet its hepatic functions and therapeutic potential remain poorly understood. This study investigated whether pharmacological activation of GPR39 protects against MASLD/MASH and promotes regression of established disease. The selective GPR39 agonist TM-N1324 was evaluated in diet-induced models of MASLD/MASH, including preventive and disease-regression settings. Systemic and liver-specific effects were assessed and hepatic pathway activation was examined. GPR39 dependency, sex dependency, and body-weight dependency were evaluated by comparing treatment effects across relevant experimental groups. TM-N1324 robustly protected against MASLD/MASH and promoted regression of established disease. Treatment improved features of the metabolic syndrome, including glucose tolerance, cholesterol metabolism, adiposity, and respiratory exchange ratio, consistent with a shift in whole-body substrate utilization toward fat, while maintaining favorable circulating triglyceride profiles. In the liver, TM-N1324 enhanced ERK1/2 signaling and SREBP2, increased hepatic VLDL levels, reduced hepatic triglycerides, and suppressed ApoB. TM-N1324 increased hepatic PARylation, and intact hepatocyte NAD+ metabolism was required for the liver-protective effects. Hepatic responses were mediated by GPR39 and were independent of sex and body weight. Pharmacological activation of GPR39 with TM-N1324 protects against MASLD/MASH, promotes regression of established disease, and improves key features of metabolic syndrome. These findings provide evidence that GPR39 is a therapeutically actionable target in MASLD/MASH and support further development of GPR39 agonism as a treatment strategy for metabolic liver disease.