Ionizing radiation induces significant oxidative stress, immune dysregulation, and cellular injury. Conventional chemical radioprotectants usually exhibit considerable toxicity and undesirable side effects, thereby restricting their applicability for prolonged administration. This study aimed to assess the radioprotective efficacy of vinegar powder (VP), a natural and nontoxic agent with potential for long-term administration. Male Kunming mice were randomly allocated into 6 groups and orally administered saline, leucogen (12 mg/kg), and VP at doses of 1.35, 2.7, or 5.4 g/kg for 30 consecutive days. Except for the control group, all mice were subjected to 6 Gy of 60Coγ-irradiation to establish a radiation injury model. Compared with the irradiated model group, VP treatment significantly increased white blood cell count by 36.69% and bone marrow DNA content by 27.65%, demonstrating potent radioprotective effects. VP also effectively restored radiation-induced depletion of reduced glutathione and suppressed malondialdehyde accumulation. Histopathological analysis of the spleen and liver revealed that VP administration substantially preserved tissue architecture compared with the radiation-damaged model group. Furthermore, network pharmacology and molecular validation were employed to elucidate the radioprotective mechanisms of VP. Bioinformatic analysis indicated that VP primarily modulated the apoptosis and NF-κB (p65) signaling pathways, targeting key molecules including RELA, Bcl-2, IKBKB, PARP1, XIAP, and CFLAR. Western blot analysis confirmed that VP alleviated radiation-induced oxidative damage by suppressing NF-κB (p65) and Bax expression while upregulating Bcl-2. Collectively, VP effectively ameliorated radiation-induced oxidative stress, hematopoietic dysfunction, and tissue damage in mice, highlighting its promise as a novel, naturally derived radioprotective agent.
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