Investigating Khat (Catha edulis Forsk) bioactive compounds for HMG-CoA Reductase inhibition and hyperlipidemia management

<ns3:p> Background Hyperlipidemia is a major risk factor for cardiovascular diseases and other metabolic disorders. Plant-derived compounds are increasingly being explored for their potential lipid-lowering effects. This study investigated the antihyperlipidemic and HMG-CoA reductase inhibitory potential of lyophilized <ns3:italic>Catha edulis</ns3:italic> (khat) leaf extract through experimental and in silico approaches. Methods Fresh <ns3:italic>Catha edulis</ns3:italic> leaves were extracted using 70% ethanol, concentrated, and lyophilized. Gas Chromatography-Mass Spectrometry (GC–MS) was employed to identify phytochemicals, which were then subjected to molecular docking against HMG-CoA reductase. Male albino Wistar rats were induced with hyperlipidemia using a high-fat diet for 30 days and divided into seven groups (n=6). Groups received khat extract (100, 200, and 400 mg/kg), atorvastatin (10 mg/kg), or phentermine (10 mg/kg) orally for 60 days. Lipid profiles were measured, and data were analyzed using one-way ANOVA (p&lt;0.05). Results GC–MS identified 21 bioactive compounds including fatty acid esters, phenolics and terpenoids. Molecular docking revealed strong interactions between HMG-CoA reductase and khat-derived 2,4-di-tert-butylphenol (−6.7 kcal/mol). Experimentally, khat significantly reduced total cholesterol, triglycerides, and LDL-C while increasing HDL-C in a dose-dependent manner. High-dose khat (400 mg/kg) exhibited comparable lipid-lowering effects to atorvastatin. Conclusion Lyophilized khat extract exhibits promising antihyperlipidemic activity through modulation of lipid metabolism and inhibition of HMG-CoA reductase. However, caution is needed due to potential toxicity of cathinone. Future research should isolate non-toxic active constituents and evaluate pharmacokinetic properties. </ns3:p>