Argan Oil Mitigates Olanzapine‐Induced Weight Gain and Metabolic Alterations: An In Silico and Experimental Study

ABSTRACT Olanzapine, a commonly prescribed antipsychotic, is associated with metabolic disturbances, such as weight gain, dyslipidemia, and glucose dysregulation. Argan oil, a traditional Amazigh dietary component, is known for its anti‐obesity and lipid‐lowering effects, but its influence on olanzapine‐induced weight gain remains unexplored. This study aimed to evaluate the pharmacological role of Argan oil against olanzapine‐induced weight gain and metabolic disturbances using in silico and in vivo approaches. Sixteen bioactives from Argan oil were screened for gastrointestinal absorption, and potential protein targets were predicted, yielding 111 protein targets across 124 metabolic pathways. Molecular docking revealed ligand–target interactions, while an in vitro pancreatic lipase inhibition assay examined anti‐obesity activity, and in vivo studies evaluated body weight, food intake, activity, glucose, lipid profile, and histology. Among the compounds, epicatechin, a key bioactive, interacted with 105 proteins, notably HMGCR (cholesterol biosynthesis) and HSD11B1 (glucocorticoid metabolism), which were identified as key modulators. Docking showed strong epicatechin binding to HMGCR, while Argan oil exhibited lipase inhibition (IC 50 = 66.54 µg/mL). In vivo, it reduced olanzapine‐induced weight gain, hyperglycemia, and dyslipidemia, improving metabolic and behavioral outcomes, highlighting its potential as a nutraceutical against antipsychotic‐induced metabolic syndrome.