Nano-Diosmin mitigates EAC-induced renal injury through Nrf2-mediated antioxidant activation and NF-κB-dependent apoptotic suppression.

The present study provides the first evidence of the anticancer-associated renoprotective efficacy of diosmin (DI) delivered via chitosan nanoparticles (DI-CHNPs) in mice bearing Ehrlich ascites carcinoma (EAC). Sixty female Swiss albino mice were divided into six groups: controls, DI, DI-CHNPs, EAC, EAC+DI, and EAC+DI-CHNPs. Treatments involved DI or DI-CHNPs (100 mg/kg/day) for 20 days with or without tumor induction. DI-CHNPs significantly reduced tumor burden, as evidenced by lower body weight gain, abdominal circumference, tumor volume, and viable tumor cell count, and these effects were superior to free DI. DI-CHNPs also prolonged survival and improved renal function markers (urea, creatinine, electrolytes), indicating that attenuation of tumor progression was accompanied by reduced secondary renal injury. Antioxidant defenses in kidney tissues were strengthened through increased superoxide dismutase, catalase, glutathione peroxidase activities, and reduced glutathione levels, alongside reduced malondialdehyde. DI-CHNPs activated the Nrf2/HO-1/NQO1 pathway while down-regulated the inflammatory pathways controlling genes (Tgfb 1, Nfkb 1, Il6) and pro-apoptotic markers (Bax, Caspase-3), with increased Bcl-2 expression. Histopathological and ultrastructural analyses confirmed superior renal protection compared with DI. Molecular docking provided in silico supportive evidence for DI interaction with Nrf2, NF-κB, caspase-3, and TGF-β-related molecular targets involved in oxidative stress, inflammation, and apoptosis. Overall, the findings suggest that nanoparticle formulation enhanced the therapeutic performance of DI, likely through improved stability and sustained-release properties, resulting in superior antitumor efficacy and attenuation of tumor-associated renal injury.