Nano-Melittin Attenuates Zearalenone-Induced Ovarian Toxicity by Modulating the Inflammatory–Apoptotic–Steroidogenic Axis in Rats

Background: Zearalenone (ZEA) is a potent estrogenic mycotoxin that adversely affects the female reproductive system, causing hormonal imbalance, uterine enlargement, structural changes in the reproductive tract, and reduced fertility. This study evaluated the protective effects of melittin-loaded chitosan nanoparticles (MEL-NPs) against ZEA-induced ovarian toxicity in female rats. Methods: Forty-eight adult female Wistar rats (180–200 g) were divided into four groups: Control, ZEA, ZEA + MEL, and ZEA + MEL-NPs. ZEA (2.7 mg/kg b.w.) was administered orally twice weekly for two weeks. MEL and MEL-NPs (40 μg/kg b.w.) were given orally three times weekly for one month. Serum biochemical parameters were measured, and ovarian tissues were examined grossly and histopathologically. qRT-PCR was performed to assess mRNA expression of inflammatory markers (TNF-α, IL-6, IL-1β), apoptotic marker (Caspase-3), and steroidogenic enzyme (CYP19A1). Results: ZEA exposure induced significant ovarian toxicity, evidenced by increased TNF-α, IL-6, IL-1β, LH, FSH, CA-125, and Caspase-3, along with decreased progesterone, antioxidant capacity, and CYP19A1 expression. Histopathology revealed ovarian atrophy, follicular degeneration, and fibrosis. Treatment with MEL-NPs markedly reversed these alterations, normalizing cytokine and hormonal profiles, restoring CYP19A1 expression, and improving ovarian morphology. MEL-NPs demonstrated superior protective effects compared to free MEL. Conclusions: MEL-NPs effectively ameliorate ZEA-induced ovarian toxicity by restoring hormonal balance, enhancing antioxidant defense, and reducing inflammation and apoptosis. These findings suggest that MEL-NPs could be a promising therapeutic strategy for preventing mycotoxin-induced ovarian dysfunction.