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Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated fatty liver disease (MASLD), is characterized by disrupted lipid metabolism and persistent inflammation, which can lead to cirrhosis and hepatocellular carcinoma. The novel pan-peroxisome proliferator-activated receptor (PPAR) agonist 1d has been previously shown to alleviate insulin resistance and hepatic steatosis in type 2 diabetic (T2DM) mice; however, its mechanism of action remains unclear. Our integrated in vitro and in vivo findings demonstrate that compound 1d significantly improves disordered hepatic lipid metabolism by modulating the AMPK-ACC-PPARα axis—specifically, by upregulating AMPK expression and phosphorylation, inhibiting ACC activity, downregulating FASN, and upregulating PPARα. Concurrently, 1d exhibits potent anti-inflammatory effects in both settings, effectively mitigating hepatic inflammation in a MASH mouse model. Therefore, compound 1d improves lipid metabolism through the AMPK-ACC-PPARα axis and additionally provides an anti-inflammatory benefit, highlighting its potential as a novel therapeutic candidate for MASH.
Bai et al. (Mon,) studied this question.