Perillaldehyde mitigates ionizing radiation-induced intestinal injury by inhibiting ferroptosis via the Nrf2 signaling pathway

Abstract The gastrointestinal tract is a rapidly self-renewing system and is thus highly sensitive to ionizing radiation (IR). Unfortunately, methods for preventing and treating IR-induced gastrointestinal syndrome are limited. Volatile monoterpenoid perillaldehyde (PAH) is the major component of the essential oil extracted from perilla plants and has been demonstrated to have antioxidant, anti-inflammatory, antimicrobial activity, and antitumor effects. However, its role in preventing or alleviating radiation-induced injuries remains unknown. In this study, PAH prolonged the survival time and attenuated radiation-induced intestinal injury in whole abdominal lethally irradiated mice. PAH treatment also promoted the survival of crypt cells, attenuated radiation-induced DNA damage, and mitigated intestinal barrier damage in irradiated mice. The radioprotective effects of PAH in intestinal crypt organoids and human intestinal epithelial cell line (HIEC-6) were also identified. PAH-mediated radioprotection was associated with the upregulation of Nrf2, activation of the antioxidant pathway, and inhibition of ferroptosis. Notably, treatment with the Nrf2 inhibitor ML385 abolished the protective effects of PAH, indicating that Nrf2 activation is essential for PAH activity. The findings of this study collectively suggest that PAH is a promising therapeutic strategy for IR-induced intestinal injury.