DTMB attenuates hepatic inflammation and lipid dysregulation via PPAR-γ modulation in diet-induced steatohepatitis

Steatohepatitis is a progressive liver disease characterized by hepatic steatosis, chronic inflammation, and fibrotic remodeling, ultimately leading to cirrhosis and hepatocellular carcinoma. Despite recent therapeutic advances, strategies that effectively target both inflammatory and metabolic dysfunction without exacerbating metabolic liabilities remain limited. Here, we investigated the effects of [4-(4-methoxyphenyl)-8-methyl-2-oxochromen-7-yl] (2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (DTMB), a selective modulator of Peroxisome Proliferator-activated Receptor gamma (PPAR-γ), in multiple diet-induced models of steatohepatitis. DTMB treatment reduced hepatic inflammation by suppressing NF-κB-driven inflammatory signaling. Concurrently, DTMB attenuated hepatic steatosis in association with increased adipose triglyceride Lipase (ATGL) expression. Notably, these effects were observed without the weight gain and lipid storage typically associated with full PPAR-γ agonists. Together, these findings suggest that DTMB functions as a selective PPAR-γ modulator that uncouples anti-inflammatory and lipid-regulatory benefits from adverse metabolic effects, highlighting its therapeutic potential for steatohepatitis.