<i>In Vivo</i> and <i>In Silico</i> Evaluation of a Polyphenol Fraction Extracted From <i>Argania spinosa</i> L. Press‐Cake Against Ethylene Glycol‐Induced Calcium Oxalate Urolithiasis in Rats: Biochemical, Histopathological, and Molecular Modeling Analyses

Abstract

ABSTRACT In Morocco, Argania spinosa L. is traditionally used to treat kidney‐related disorders such as urolithiasis. However, its anti‐urolithiatic potential remains poorly documented from a scientific standpoint. This study aimed to evaluate the anti‐crystallization, nephroprotective, and hepatoprotective effects of a polyphenol‐rich fraction from A. spinosa press cake in an ethylene glycol‐induced urolithiasis rat model, and to explore its pharmacokinetic profile and molecular interactions through in silico analyses. Urolithiasis was induced in male Wistar rats by administering 0.75% ethylene glycol in drinking water for 15 days. Treatment groups received either the polyphenol‐rich fraction or cystone. Biochemical analyses of urine and blood were performed, and renal and hepatic tissues were subjected to histopathological examination. In silico studies included molecular docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions to evaluate pharmacokinetic properties and target interactions. Ethylene glycol administration led to a significant increase in urinary pH and protein levels, reduced urinary magnesium, and caused renal and hepatic tissue damage. Treatment with the polyphenol‐rich fraction significantly corrected these alterations ( p &lt; 0.05), reduced histological lesions, and restored biochemical parameters. Molecular docking revealed high binding affinities between the major polyphenols and targets involved in urolithiasis pathogenesis. ADMET analyses suggested favorable pharmacokinetic profiles and low toxicity. The polyphenol‐rich fraction of A. spinosa press cake shows promising protective effects against ethylene glycol‐induced kidney stone formation and associated organ toxicity. These findings highlight its potential as a natural therapeutic agent for the prevention and management of urolithiasis and renal dysfunction.