A Novel CYP2E1 Inhibitor, 4-Methyl-5-Acetylthiazole (Q11), Alleviates Obesity Via Modulating Adipose Inflammation and...

Obesity is a major global health challenge characterized by chronic low-grade inflammation and impaired mitochondrial homeostasis. Although cytochrome P450 2E1 (CYP2E1) is implicated in oxidative stress and inflammatory signaling, its contribution to adipocyte dysfunction during obesity remains insufficiently defined. Here, we evaluate the functional role of CYP2E1 in obesity and the therapeutic potential of a highly selective CYP2E1 inhibitor, 4-methyl-5-acetylthiazole (Q11). High-fat diet-induced obese mice exhibited markedly elevated CYP2E1 expression and activity, which positively correlated with increased adiposity, hepatic steatosis, and mitochondrial dysfunction. Pharmacological inhibition of CYP2E1 by Q11 significantly attenuated body weight gain, improved hepatic lipid accumulation, and reduced inflammatory responses without affecting food intake, suggesting that its metabolic benefits are mediated through enhanced energy expenditure. Mechanistically, Q11 restored mitochondrial integrity by increasing oxygen consumption, normalizing membrane potential, promoting mitochondrial biogenesis, and improving fusion dynamics, accompanied by activation of the AMP-activated protein kinase/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha pathway. Collectively, these findings identify CYP2E1 as a previously unrecognized regulator of obesity-associated metabolic dysfunction and establish Q11 as a promising therapeutic candidate that concurrently suppresses inflammation and reinstates mitochondrial homeostasis. This work provides a mechanistic and translational foundation for targeting CYP2E1 in obesity and related metabolic disorders.