Exploring Ceratonia siliqua Seeds Oil and Metformin for PCOS Treatment: Mechanistic Insights into PI3K/AKT Pathway, Inflammation, and Oxidative Stress

Abstract Introduction: Polycystic ovary syndrome (PCOS) is a leading cause of infertility, irregular menstrual cycles, and anovulation in women. This study aimed to investigate the therapeutic effects of Ceratonia siliqua L. seed oil (CSSO) on PCOS in rats. Subjects and Methods: In this experimental study, 70 rats were divided into seven groups ( n = 10/group) and studied over 50 days: The healthy control, patient (PCOS), metformin (MET + PCOS), 100 and 200 mg/kg CSSO treatment (100 and 200 CSSO + PCOS), and synergistic (MET + 100 and 200CSSO + PCOS) groups. Levels of luteinizing hormone, follicle-stimulating hormone, progesterone, and testosterone were measured. Serum levels of inflammatory cytokines and antioxidant parameters were assessed. Total antioxidant capacity and lipid peroxidation levels in ovarian tissue were analyzed. Gene expression of GLUT-4, AKT, PI3K, and PTEN was evaluated using real-time polymerase chain reaction, and their protein expression was assessed by western blotting. The expression of Ki-67 protein and apoptosis were evaluated using immunohistochemistry. Results: CSSO, especially in combination with MET, significantly improved hormonal, inflammatory, and antioxidant parameters compared to the PCOS and MET groups. In the synergistic groups, CSSO enhanced apoptosis of granulosa cells by activating the PI3K/AKT pathway, leading to an increase in Ki-67-positive cells. CSSO extract, particularly when used in combination with MET, can enhance the hypothalamic–pituitary–ovary axis function through its anti-inflammatory and antioxidant effects. Conclusion: CSSO can promote apoptosis in cystic granulosa cells, making it a potential therapeutic agent for PCOS.