DTMB mitigates diet-induced metabolic dysfunction-associated steatohepatitis by targeting inflammation and lipid metabolism

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), and is characterized by steatosis, inflammation, and fibrosis. Without effective treatment, MASH can progress to cirrhosis and hepatocellular carcinoma. Despite recent therapeutic advances, there remains an unmet need for agents that address both chronic inflammation and metabolic dysfunction. Here, we investigate the effects of DTMB, a peroxisome proliferator-activated receptor gamma (PPAR-γ)-modulating compound, in multiple diet-induced models of MASLD and MASH. DTMB treatment was associated with reduced hepatic inflammation, accompanied by suppression of NF-κB/NLRP3 inflammasome-related signaling and attenuation of hepatic steatosis, alongside increased adipose triglyceride lipase (ATGL) expression. Notably, unlike full PPAR-γ agonists, DTMB exerts these beneficial effects without causing weight gain. Collectively, our study highlights the promising protective effect of DTMB as a selective PPAR-γ modulator for treating metabolic dysfunction-associated liver disease.