EGCG-mediated selenium nanoparticles protect against 5-fluorouracil-induced cardiotoxicity via Nrf2/Keap1 signaling

5-Fluorouracil (5-FU) is a widely used anticancer drug; however, its clinical application is limited by severe adverse effects, particularly cardiotoxicity. This study investigated the cardioprotective potential of epigallocatechin gallat-mediated selenium nanoparticles (EGCG-SeNPs) against 5-FU-induced cardiac injury in rats and explored the underlying mechanisms, with a specific focus on comparing the efficacy of the combined therapy versus EGCG or selenium monotherapy. In silico molecular docking was performed to evaluate the interaction of EGCG with inducible nitric oxide synthase (iNOS), glutathione S-transferase (GST), and tumor necrosis factor-α (TNF-α). Thirty-five male Wistar rats were randomly assigned to five groups: control, 5-FU, Na_₂SeO_₃&5-FU, EGCG&5-FU, and EGCG-SeNPs&5-FU. Cardiotoxicity was induced by intraperitoneal administration of 5-FU (30 mg/kg) for five consecutive days, while treatments were administered orally for 21 days. Cardiac injury biomarkers, oxidative stress parameters, inflammatory mediators, and apoptotic markers were evaluated using biochemical assays, ELISA, qRT-PCR, immunohistochemistry for Nrf2/Keap1 signaling, and histopathological examination. 5-FU induced significant cardiotoxicity, evidenced by elevated CK-MB, LDH, and troponin levels; increased lipid peroxidation; depletion of antioxidant defenses; activation of inflammatory cytokines (TNF-α, IL-1β, and NF-kB); suppression of IL-10; and enhanced apoptosis, accompanied by myocardial histopathological damage and reduced Nrf2 immunoreactivity. Treatment with EGCG or sodium selenite attenuated these alterations, while EGCG-SeNPs exerted cardioprotective effects, restoring redox balance, suppressing inflammation and apoptosis, modulating Nrf2/Keap1 signaling, and preserving myocardial architecture. EGCG-mediated selenium nanoparticles exhibit potent cardioprotective effects through antioxidant, anti-inflammatory, and antiapoptotic mechanisms. These findings highlight the therapeutic potential of EGCG-SeNPs as a promising cardioprotective strategy during 5-FU chemotherapy.