Nrf2–ARE pathway activation underpins hinokitiol’s protection against radiation-induced hematological, hepatic, and inflammatory injury

Background Ionizing radiation (IR) disrupts redox balance and causes tissue injury through reactive oxygen species. Although the Nrf2–ARE pathway governs antioxidant defense, effective radioprotective activators remain limited. Hinokitiol, a natural antioxidant and anti-inflammatory tropolone, has not been previously evaluated in vivo for Nrf2-mediated radioprotection.Methods Forty male albino rats were divided into four groups: control, irradiated (8 Gy, fractionated), hinokitiol-only, and hinokitiol-pretreated + irradiated (Hinokitiol (10 mg/kg/day), by oral gavage). All parameters were assessed 24 hours after the final irradiation session.Results IR caused marked hematological suppression (reductions in RBCs, WBCs, platelets), hepatocellular injury (elevated ALT, reduced total protein), oxidative stress (increased MDA, NO, MPO), apoptosis, and downregulation of Nrf2-dependent genes. Hinokitiol pretreatment partially restored hematological parameters (platelets improved by over 20%, p = 0.026), reduced ALT by more than half, lowered NO and MPO levels, restored GSH, SOD, and CAT activities by more than 60% (p < 0.001), and decreased DNA fragmentation by nearly 50% (p < 0.01). Gene expression analysis revealed significant (p < 0.01) upregulation of Ho-1 , Nqo1, and Txnrd1 and significant (p < 0.01) suppression of Nf-κB and Tnf-α, consistent with Nrf2-ARE pathway activation and attenuation of inflammatory signaling. Histological analysis confirmed preserved hepatic architecture, supporting the liver’s sensitivity to systemic oxidative injury and highlighting Hinokitiol’s hepatic accumulation and protective effects.Conclusion These findings suggest, for the first time, that hinokitiol may activate the Nrf2–ARE pathway to counteract IR-induced oxidative stress, inflammation, and apoptosis, resulting in systemic protection. Hinokitiol emerges as a promising radioprotective candidate, warranting further investigation into its pharmacokinetics, toxicity profile, and translational potential as an adjunct in radiotherapy and other radiation exposure scenarios.