Mechanistic insights into the renoprotective effects of rutin-loaded selenium nanoparticles against 5-fluorouracil toxicity via regulation of Nrf2/Keap1, NF-κB/NLRP3, and PERK pathways.

5-Fluorouracil (5-FU) is a mainstay chemotherapeutic compound in the management of solid neoplasia; however, its clinical application is frequently restricted by significant nephrotoxicity. This study was performed to assess the renal protective impact of rutin (RUT), sodium selenite (Na₂SeO₃), and green-synthesized selenium nanoparticles (SeNPs) functionalized with rutin (RUT-SeNPs) in an animal model of 5-FU-provoked renal injury. Thirty-five rats were divided arbitrarily into 5 equal groups: normal control, 5-FU, 5-FU&Na₂SeO₃, 5-FU&RUT, and 5-FU&RUT-SeNPs. Application of 5-FU caused pronounced renal dysfunction, characterized by marked elevations in conventional and early kidney injury biomarkers, profound oxidative stress, activation of inflammatory signaling routes including NF-κB, and stimulation of apoptotic cascades, together with depletion of endogenous antioxidant defenses. Although treatment with RUT or Na₂SeO₃ afforded partial renal protection, RUT-SeNPs demonstrated superior efficacy by markedly attenuating functional, oxidative, inflammatory, and apoptotic derangements and restoring antioxidant homeostasis toward physiological levels. These biological and molecular findings were substantiated by histopathological and immunohistochemical analyses, which revealed preservation of renal architecture and a significant reduction in inflammatory and apoptotic lesions. Collectively, these results highlight RUT-SeNPs as a promising nanotherapeutic approach for alleviating 5-FU-induced nephrotoxicity.