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<p>Doxorubicin (DOX), a cornerstone chemotherapeutic, induces dose-limiting nephrotoxicity through NOX-4-mediated oxidative stress, inflammatory signalling, and apoptosis, thereby compromising its long-term clinical utility. This study investigated whether 5,4′-dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone (DDR), a bioactive flavonoid, protects against chronic DOX-induced renal injury. To evaluate DDR’s renoprotective efficacy and elucidate its mechanistic involvement of NOX-4, NRF2, and apoptotic pathways. Male Swiss albino mice (<i>n</i> = 6/group) received: control vehicle, DOX (2.5&#xa0;mg/kg i.p., weekly × 6 weeks), DOX + DDR (25 or 50&#xa0;mg/kg i.p., twice weekly), or DDR alone. Renal function (creatinine, urea, NGAL, KIM-1), oxidative stress markers (MDA, SOD, CAT, GSH), cytokines (pNFκB, TNF-α, IL-6, IL-1β), and protein expression (NOX-4, NRF2, BCL2, BCL-XL, Caspase-3) were quantified. Histopathology employed H&amp;E and Masson’s trichrome with semi-quantitative injury scoring. DOX induced severe nephrotoxicity (serum creatinine ↑347%, tubular injury score 14.8 ± 1.4, <i>p</i> &lt; 0.001), characterized by NOX-4 overexpression, NRF2 suppression, and apoptosis (Caspase-3 ↑412%). DDR elicited dose-dependent protection; high-dose DDR restored renal function (creatinine ↓78%), normalized histopathology (score 2.8 ± 0.9, <i>p</i> &lt; 0.001), suppressed NOX and reactivated NRF2, and prevented apoptosis. DDR provides potent, mechanistically defined renoprotection against DOX nephrotoxicity through multi-target modulation of oxidative, inflammatory, and apoptotic pathways. These preclinical findings support DDR’s development as a clinically translatable chemotherapeutic adjuvant (Human equivalent dose: 2–4&#xa0;mg/kg).</p>

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Amelioration of doxorubicin-mediated nephrotoxicity through antioxidant and anti-apoptotic mechanisms of 5,4′-dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone

  • 期刊论文

  • 发表日期：

    2026年2月21日

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  • Peramaiyan Rajendran,
  • Abdullah Alzahrani,
  • Ramya Sekar,
  • Gamal M. Bekhet,
  • Rajkapoor Balasubramanian

摘要

Doxorubicin (DOX), a cornerstone chemotherapeutic, induces dose-limiting nephrotoxicity through NOX-4-mediated oxidative stress, inflammatory signalling, and apoptosis, thereby compromising its long-term clinical utility. This study investigated whether 5,4′-dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone (DDR), a bioactive flavonoid, protects against chronic DOX-induced renal injury. To evaluate DDR’s renoprotective efficacy and elucidate its mechanistic involvement of NOX-4, NRF2, and apoptotic pathways. Male Swiss albino mice (n = 6/group) received: control vehicle, DOX (2.5 mg/kg i.p., weekly × 6 weeks), DOX + DDR (25 or 50 mg/kg i.p., twice weekly), or DDR alone. Renal function (creatinine, urea, NGAL, KIM-1), oxidative stress markers (MDA, SOD, CAT, GSH), cytokines (pNFκB, TNF-α, IL-6, IL-1β), and protein expression (NOX-4, NRF2, BCL2, BCL-XL, Caspase-3) were quantified. Histopathology employed H&E and Masson’s trichrome with semi-quantitative injury scoring. DOX induced severe nephrotoxicity (serum creatinine ↑347%, tubular injury score 14.8 ± 1.4, p < 0.001), characterized by NOX-4 overexpression, NRF2 suppression, and apoptosis (Caspase-3 ↑412%). DDR elicited dose-dependent protection; high-dose DDR restored renal function (creatinine ↓78%), normalized histopathology (score 2.8 ± 0.9, p < 0.001), suppressed NOX and reactivated NRF2, and prevented apoptosis. DDR provides potent, mechanistically defined renoprotection against DOX nephrotoxicity through multi-target modulation of oxidative, inflammatory, and apoptotic pathways. These preclinical findings support DDR’s development as a clinically translatable chemotherapeutic adjuvant (Human equivalent dose: 2–4 mg/kg).