Oxazolidine derivative ameliorates diet-induced non-alcoholic fatty liver disease by modulating PI3K/AKT signaling and metabolic homeostasis

Biochem Pharmacol. 2026 Sep 9:118451. doi: 10.1016/j.bcp.2026.118451. Online ahead of print.

ABSTRACT

The most common type of chronic liver disease is non-alcoholic fatty liver disease (NAFLD), which has become a significant worldwide health concern. Western eating patterns are characterized by diets high in fats and sugar, which disrupt redox balance, promote inflammatory responses, and impair normal liver function. Effective pharmacological treatments for NAFLD and non-alcoholic steatohepatitis (NASH) are still unavailable, despite their increasing occurrence. Derivatives of oxazolidine are known for a variety of pharmacological properties, including as antidiabetic, anti-inflammatory, and antioxidant actions. In this work, we assessed the potential of AP4 (4-(3-(4-nitrophenyl)isoxazolidin-4-yl)benzene-1,2-diol) as a treatment for lipid metabolic dysfunction and insulin resistance. According to preliminary in vitro studies, AP4 efficiently stabilized RBC membranes, reduced α-glucosidase activity, and showed vigorous antioxidant activity in ABTS and DPPH assays. To evaluate the in vivo effectiveness of AP4, a zebrafish model of NAFLD was later established using a high-sugar, high-fat feeding regimen. To clarify its mode of action, biochemical, histological, gene expression, and network pharmacology techniques were used. Long-term dietary exposure to AP4 significantly reduced hepatic lipid accumulation, enhanced insulin sensitivity, and lowered circulating glucose and hepatic triglyceride levels. These protective effects were linked to modulation of PI3K/AKT signaling and alterations in lipid-regulatory pathways, according to mechanistic studies. The results show that AP4 slows diet-induced NAFLD and may be a promising metabolic liver disease drug.

PMID:42716137 | DOI:10.1016/j.bcp.2026.118451