Valproic acid alleviates abdominal irradiation-induced intestinal injury in mice through anti-inflammatory and barrier-preserving effects.

Radiation-induced intestinal injury is a major complication of abdominal radiotherapy; however, effective protective strategies remain limited. To overcome the systemic limitations of total body irradiation models, we developed a localized abdominal irradiation (ABI) mouse model, enabling targeted evaluation of intestinal damage. Using this model, we investigated the protective effects of valproic acid (VPA), a histone deacetylase inhibitor with known anti-inflammatory and cytoprotective properties, against radiation-induced intestinal injury. VPA administration before irradiation mitigated weight loss, preserved villus structure, and improved the villus-to-crypt ratio. Immunohistochemical analyses revealed enhanced epithelial regeneration, with increased Ki-67-positive cell counts in the intestinal mucosa. The inflammatory and oxidative stress marker levels were significantly lower in the VPA group than in the vehicle group. Additionally, intestinal barrier function was preserved, as evidenced by decreased fluorescein isothiocyanate-dextran permeability. These protective effects were most pronounced when VPA was administered prior to irradiation, suggesting that early intervention is crucial for mitigating acute radiation damage. Our findings highlight the usefulness of the ABI model for assessing intestinal injury with high specificity. The results support the potential of VPA as an effective radioprotective agent in abdominal radiotherapy and warrant further investigation into its clinical application, optimal dosing, and underlying action mechanisms.