Thiazol-sulfonyl derivative KM9 mitigates hyperglycemia-associated steatotic liver injury in in-vitro and in-vivo models

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health challenge worldwide, strongly connected to hyperglycemia (HG). This study investigates the therapeutic potential of 4-methyl-N-(6-methyl-1,3-benzothiazol-2-yl) benzene-1-sulfonamide (named KM9), a novel compound consisting of thiazol and sulfonyl groups, for HG-associated MASLD. In silico analysis using network pharmacology verified that KM9 is involved in lipid metabolism and insulin signaling pathways. In vitro and in vivo studies using HepG2 cells and zebrafish embryos demonstrated the cytotoxicity and effective dose of KM9. These studies further revealed its ability to reduce oxidative stress indicators, including reactive oxygen species (ROS), apoptosis, and lipid peroxidation (LPO) induced by alloxan (ALN). In ALN-exposed zebrafish, KM9 significantly reduced glucose levels and enhanced glucose uptake. It also lowered lipid accumulation, cholesterol, and triglyceride levels. KM9 exhibited anti-inflammatory effects by reducing macrophage localization and increased the activity of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx). Furthermore, KM9 regulated genes associated with lipogenesis (fasn, srebp1), inflammation (il-6, tnf-α), and insulin receptor expression (ins, insra1, insrb1). These findings demonstrate that KM9 exerts multifaceted protective effects, which collectively decrease liver damage and improve liver health, as evidenced by histopathological analysis.