Hesperidin nanoparticle therapy confers renoprotection and antitumor effects in Ehrlich ascites carcinoma via coordinated regulation of oxidative stress, Bax/caspase-3, and NF-κB/VEGF pathways.

This study evaluated the protective effects of hesperidin (HES) encapsulated in chitosan nanoparticles (HES-CNPs) on renal injury in mice bearing Ehrlich ascites carcinoma (EAC), while promoting apoptosis in tumor cells compared to crude HES. Ninety female Swiss albino mice, aged 6 weeks and weighing 24.3 g on average, were randomly assigned to six experimental groups: (1) control; (2) HES (100 mg/kg/day, orally); (3) HES-CNPs (100 mg/kg/day, orally); (4) EAC (intraperitoneal injection of 0.2 mL EAC cell suspension, 2.5 × 10⁶ cells); (5) EAC + HES, receiving daily HES for 20 days after tumor induction; and (6) EAC + HES-CNPs, administered daily HES-CNPs for 20 days following EAC injection. HES-CNPs significantly reduced body weight, abdominal circumference, tumor volume, and viable cell count, while enhancing survival and lifespan compared to free HES. Molecular assessments further demonstrated that this treatment resulted in the lowest Bcl-2 levels, maximal induction of Bax and caspase-3, and a significant suppression of VEGF in ascitic fluid. HES-CNPs significantly improved hematological indices and normalized renal function markers, including urea, creatinine, and electrolytes. The treatment reinforced the renal antioxidant defense by elevating the activities of superoxide dismutase, catalase, and glutathione peroxidase, while reducing glutathione oxidation and malondialdehyde accumulation, and decreasing caspase-3 activity. Concurrently, HES-CNPs effectively inhibited EAC-induced upregulation of inflammatory genes, including nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and interferon-γ. Both histopathological and ultrastructural assessments revealed that HES-CNPs conferred stronger renal protection than free HES. These findings suggest that the HES in nanoparticle form mediates coordinated regulation of oxidative stress, Bax/caspase-3, and NF-κB/VEGF pathways, driving both renoprotection and antitumor effects in EAC-bearing mice.