Résumé
This study explores the therapeutic potential of Calligonum comosum extract in alleviating pregabalin (PGB)‐induced toxicity in male Wistar rats, with a focus on hepatic, renal, and reproductive health. PGB exposure led to significant biochemical disturbances, including elevated liver enzymes (AST, ALT, LDH), impaired kidney markers (urea, creatinine, uric acid), reduced reproductive hormones (testosterone, FSH, LH), and notable histopathological damage in liver, kidney, and testicular tissues. Treatment with C. comosum extract effectively restored liver and kidney functions and partially corrected hormonal imbalances. The extract reduced AST, ALT, and LDH levels by 18.5%, 25.2%, and 13.7%, respectively. Similarly, urea, creatinine, and uric acid decreased by 30.3%, 38.0%, and 15.2%. Testosterone and LH levels improved, suggesting enhanced reproductive recovery. Histological analyses confirmed reduced inflammation, necrosis, and congestion in treated tissues. Supporting these findings, in silico docking studies showed strong interactions between C. comosum phytochemicals and molecular targets linked to toxicity pathways. Quercetin demonstrated the strongest binding (−8.1 to −9.2 kcal/mol), particularly with LXR‐α and GLUT‐1. Rutin showed the highest affinity for GnRH1‐R (−10.4 kcal/mol), while caffeic acid, gallic acid, and chlorogenic acid also exhibited strong interactions, especially with β2 AR (−8.9 kcal/mol). In contrast, PGB displayed weaker binding (−6.0 kcal/mol). These results highlight the protective effects of C. comosum and support its potential as a natural remedy for mitigating PGB‐induced hepatorenal and reproductive toxicity.