Perillaldehyde Mitigates Ionizing Radiation‐Induced Intestinal Injury by Inhibiting Ferroptosis via the Nrf2 Signaling Pathway

Scope Gastrointestinal toxicity is one of the major side effects of abdominopelvic tumor radiotherapy. Studies have shown that perillaldehyde (PAH) has antioxidant, antiinflammatory, antimicrobial activity, and antitumor effects. This study aims to determine whether PAH has radioprotective effects on radiation‐induced intestinal injury and explore the underlying mechanisms. Methods and results C57BL/6J mice are gavaged with PAH for 7 days, then exposed to a single dose of 13 Gy X‐ray total abdominal irradiation (TAI). PAH treatment prolongs the survival time, promotes the survival of crypt cells, attenuates radiation‐induced DNA damage, and mitigates intestinal barrier damage in the irradiated mice. PAH also shows radioprotective effects in intestinal crypt organoids and human intestinal epithelial cells (HIEC‐6). PAH‐mediated radioprotection is associated with the upregulation of nuclear factor erythroid‐2 related factor 2 (Nrf2), activation of the antioxidant pathway, and inhibition of ferroptosis. Notably, treatment with the Nrf2 inhibitor ML385 abolishes the protective effects of PAH, indicating that Nrf2 activation is essential for PAH activity. Conclusion PAH inhibits ionizing radiation (IR)‐induced ferroptosis and attenuates intestinal injury after irradiation by activating Nrf2 signaling. Therefore, PAH is a promising therapeutic strategy for IR‐induced intestinal injury.