Pumpkin ( Cucurbita maxima ) seed extract ameliorates letrozole and high-fat diet-induced PCOS in rats via SIRT1/AMPK/NF-κB signaling

) in combination with a high-fat diet (HFD). Treatment groups received low and high doses of PSE (100/200 mg per kg of BW) and the standard drug metformin (150 mg per kg of BW). Biochemical and histomorphological parameters were evaluated followed by mRNA and protein expression analysis of potential molecular targets. Our findings reveal that PSE treatment restored the estrous cyclicity, improved the body weight and ameliorated dyslipidemia while normalizing the LH, FSH, estrogen, testosterone, and insulin levels. Additionally, PSE decreased liver and renal function markers, HOMA-IR, C-reactive protein, IL-1β, and TNF-α inflammatory markers. Most importantly, it improved ovarian function by upregulating the mRNA expression of SIRT1, AMPK, PGC-1α, and PPAR-γ, while downregulating FOXO1, SREBP1c, LXR-β, and NF-κB. Mechanistically, PSE improved insulin resistance, inflammation and ovarian function by activating the SIRT1-AMPK signaling pathway. Collectively, our findings reveal that PSE ameliorated PCOS symptoms, demonstrating its potential as a promising therapeutic agent for managing PCOS.