Investigation of the protective effects of hesperidin against nivolumab toxicity in rat testis tissue.

Münevver Nazlican Zengin, Osman Çiftçi, S Yildirim

Naunyn Schmiedebergs Arch Pharmacol

Nov 24, 2025

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Abstract

Nivolumab is an effective immunotherapy drug, but its long-term side effects remain unknown. This study was designed as a preventive experimental model to investigate the potential preventive and protective effects of hesperidin against testicular toxicity that may be caused by nivolumab. Thirty-two male Wistar Albino rats were used in the study (n = 8 per group). The groups were as follows: control, nivolumab (3 mg/kg), hesperidin (50 mg/kg), and nivolumab (3 mg/kg) + hesperidin (50 mg/kg). After the completion of drug administration, blood and testicular tissues were collected under anesthesia. ELISA, real-time PCR, and histopathological analyses were performed to assess the biochemical, molecular, and histopathological changes in the testicular tissue. Histopathological analysis revealed that nivolumab caused notable damage to the testicular tissue. Severe cytoplasmic expression of 8-hydroxyguanosine (8-OHdG) and Caspase-3 was observed in spermatocytes, indicating oxidative stress and apoptosis. Hesperidin administration attenuated these histopathological changes. Biochemical analysis showed that nivolumab disrupted the balance of total oxidants and antioxidants, leading to oxidative stress, whereas hesperidin enhanced antioxidant activity and reduced oxidative damage. Additionally, nivolumab significantly reduced serum testosterone levels, while hesperidin increased testosterone levels. In terms of molecular pathways, nivolumab downregulated PI3K, AKT, and MTOR expressions, disrupting this signaling cascade, while hesperidin restored these expressions to levels closer to the control group. Nivolumab also reduced PD-1 expression, but hesperidin did not alter PD-1 expression levels. This preventive experimental design demonstrated that nivolumab caused oxidative damage and histopathological changes in rat testicular tissue, whereas hesperidin provided preventive protection against these adverse effects through its antioxidant and anti-apoptotic properties.