Introduction and Objective: MASLD prevalence has increased to ~38% globally, with over 65% of people with MASLD having concomitant T2DM. This study evaluated whether combining dorzagliatin (glucokinase activator) and resmetirom (THR-β agonist) provides synergistic metabolic and hepatic benefits in a mouse model of MASLD. Methods: Male DIO mice with confirmed MASLD were randomized to receive dorzagliatin, resmetirom, or combination therapy for 6 weeks. Metabolic and hepatic outcomes were assessed via OGTT, serum biochemistry, liver histopathology (NAS score), and transcriptomic analysis. Results: Combined therapy significantly improved glucose tolerance compared with either monotherapy (P0.05). The combination group exhibited higher ΔC/ΔG ratios during early and late phases after glucose challenge, indicating enhanced first-phase and sustained insulin secretion. Dorzagliatin potentiated the triglyceride-lowering effect of resmetirom, and only the combination group showed a significant reduction in serum uric acid (P0.01). Histopathology revealed that while dorzagliatin reduced hepatic ballooning, the combination group achieved superior reduction in fibrosis and steatosis scores compared to resmetirom alone, suggesting a potent antifibrotic synergy. Conclusion: In DIO mice, dorzagliatin and resmetirom combination therapy provided additional metabolic benefits compared with monotherapy, including synergistic improvements in glycemic control, greater triglyceride reduction, and significant lowering of serum uric acid. Dorzagliatin did not compromise, and in part enhanced, resmetirom’s beneficial effects on hepatic ballooning and fibrosis. These findings highlight the potential value of dual targeting glucose and lipid metabolism for addressing the complex metabolic disturbances associated with MASH and support further investigation of combination strategies in metabolic disease. Disclosure X. Gao: Employee; Current; Hua Medicine. L. Feng: None. J. Ni: Employee; Current; Hua Medicine. F. Tang: None. L. Chen: None.
GAO et al. (Fri,) studied this question.