Background: This study investigated the hypolipidemic and hepatoprotective effects of refined soybean oil supplemented with an Ocimum basilicum L. extract, characterized by HPLC and found to be rich in caftaric, caffeic, chicoric, and rosmarinic acids. Methods: After a 12-week model of diet-induced hyperlipidemia, we examined the plasma levels of TC, TG, Glucose, HDL-C, and LDL-C and the LDL-C/HDL-C ratio using enzymatic kits. The Plasma Hepatic and Biliary Marker Analysis was analysed following standardized hospital protocols with quality-controlled instrumentation. Results: The supplementation with Basil-Enriched Oil (BEO) resulted in a notable redistribution of lipids, significantly reducing the plasma total cholesterol (−75%), triglycerides (−96%), and glucose (−22%), while enhancing their hepatic sequestration. This was accompanied by a marked improvement in the LDL-C/HDL-C ratio and a reduction in hepatic oxidative stress (measured by MDA). Importantly, BEO preserved liver structure and prevented steatosis, despite inducing an increase in adaptive hepatomegaly. Conclusions: The results reveal a dual mechanism whereby the antioxidant properties of BEO collaborate with reprogrammed lipid metabolism, promoting safe hepatic storage rather than harmful circulating levels. These findings strongly advocate for the extract’s potential as a nutraceutical for addressing hyperlipidemia and related metabolic disorders by targeting both oxidative stress and lipid imbalance. Further research is required to confirm these effects in clinical settings and to confirm its long-term efficacy.

Background: Hyperlipidemia is a major risk factor for cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), and is closely associated with oxidative stress. Opuntia ficus-indica (OFI) cladodes are recognized as a rich source of bioactive phytochemicals; however, the molecular mechanisms underlying their metabolic benefits remain incompletely understood. Objectives: This study aimed to comprehensively evaluate the hypolipidemic and hepatoprotective potential of a polyphenol-rich O. ficus-indica cladode extract (OCE) using an integrated approach combining in vivo evaluation, untargeted metabolomics (UHPLC-Orbitrap-MS/MS), molecular docking, and ADMET prediction. Methods: Hyperlipidemic mice fed a high-fat diet (HFD) were treated with OCE, while molecular docking was performed on ten major annotated phytochemicals against twelve key proteins involved in lipid metabolism and cholesterol homeostasis, including HMGCR, FAS, PPARα, PCSK9, and NPC1L1, using simvastatin as the reference compound. Results: OCE treatment significantly improved plasma and hepatic lipid profiles, improved glucose homeostasis, and markedly reduced hepatic malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. Histopathological analysis further supported a pronounced hepatoprotective effect, with a substantial reduction in hepatic steatosis. Untargeted metabolomics enabled the annotation of 102 metabolites, putatively identifying piscidic acid as the predominant phenolic constituent together with a diverse profile of flavonoids and phenolic acids. Molecular docking supported the potential contribution of these phytochemicals to the regulation of lipid metabolism through favorable interactions with multiple therapeutic targets, while ADMET prediction suggested an overall favorable pharmacokinetic and toxicity profile despite the lower intestinal permeability predicted for glycosylated derivatives. Conclusions: Overall, these findings support O. ficus-indica cladodes as a promising source of dietary bioactive compounds with potential applications in the nutritional management and prevention of hyperlipidemia and related cardiometabolic disorders.