Piperidinesulfonyl derivatives, novel CYP4A inhibitors, ameliorate hepatic lipotoxicity in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis alongside comorbidities such as obesity, type 2 diabetes mellitus (T2DM), and hypertension. With its complex and multifactorial pathogenesis, MASLD presents substantial challenges for therapeutic intervention, underscoring the need for safe and effective treatments. Cytochrome P450 4A (CYP4A) has been identified as a critical enzyme involved in oxidative metabolism, contributing significantly to the pathophysiology of MASLD. Thus, targeting CYP4A could represent a promising therapeutic strategy for this disease. In this study, we aimed to expand the therapeutic pipeline of CYP4A inhibitors by identifying and evaluating new CYP4A inhibitor derivatives. Using in silico analysis, we identified candidate inhibitors, C86 and C87, which demonstrated potent effects on CYP4A expression and enzymatic activity. Treatment with C86 and C87 effectively ameliorated lipotoxicity, reduced oxidative stress, ER stress and apoptosis, and improved insulin resistance in various MASLD models, including in vitro, in vivo, and 3D liver systems. Notably, in MASLD models of hepatic inflammation and fibrosis, both C86 and C87 improved histological and biochemical markers of liver injury. Conclusively, our findings highlight C86 and C87 as valuable candidates for expanding the MASLD treatment pipeline and underscore the critical role of CYP4A as a target for developing novel therapeutic approaches in MASLD.