Amelioration of Doxorubicin-Mediated Nephrotoxicity through Antioxidant and Anti-apoptotic Mechanisms of 5,4′-Dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone

Doxorubicin (DOX) is a potent chemotherapeutic agent whose clinical utility is limited by cumulative nephrotoxicity driven by oxidative stress, inflammation, and apoptosis. Natural flavonoids have shown promise in mitigating such adverse effects. This study evaluated the renoprotective efficacy of 5,4′-dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone (DDR) against chronic DOX-induced kidney injury, focusing on the involvement of NOX-4-mediated oxidative stress, inflammatory signalling, NRF2 antioxidant pathways, and apoptotic regulators BCL2 and Caspase-3.Male albino mice were randomized into five groups (n = 6): control, DOX (2.5 mg/kg intraperitoneally, once weekly for six weeks), DOX plus low-dose DDR (25 mg/kg, twice weekly), DOX plus high-dose DDR (50 mg/kg, twice weekly), and DDR alone. Renal function was assessed via serum creatinine, urea, and biomarkers NGAL and KIM-1. Oxidative stress markers (MDA, GSH, SOD, CAT), pro-inflammatory cytokines (pNFκB,TNF-α, IL-6 and IL-1β), and protein expression of NOX-4, NRF2, BCL2, and Caspase-3 were quantified by biochemical assays, ELISA, immunohistochemistry, and Western blotting. Kidney tissues underwent histopathological evaluation using hematoxylin and eosin and Masson’s trichrome staining. DOX administration induced significant renal impairment, characterized by elevated MDA, NOX-4, pNFκB,TNF-α, IL-6, Il-1β and Caspase-3 levels, alongside reduced antioxidant enzyme activities and BCL2 expression. Activation of signaling and suppression of NRF2 correlated with marked glomerular and tubular injury. DDR treatment ameliorated these effects in a dose-dependent manner; high-dose DDR significantly improved renal function, diminished oxidative and inflammatory mediators, enhanced antioxidant defenses, suppressed NOX-4 and upregulated NRF2 and BCL2, resulting in preserved renal histology. DDR confers dose-dependent nephroprotection against chronic DOX-induced toxicity by modulating oxidative stress, inflammation, and apoptosis. These findings advocate DDR’s potential as an adjunctive agent to alleviate chemotherapy-associated renal damage.