Green tea derivative (-)-epigallocatechin-3-gallate (EGCG) confers protection against ionizing radiation-induced intestinal epithelial cell death both in vitro and in vivo

Abstract

Radiation-induced intestinal injury (RIII) occurs during instances of intentional or accidental radiation exposure. However, there are few effective treatments available for the prevention or mitigation of RIII currently. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, possesses potent antioxidant activity and has been shown to be effective in ameliorating many oxidative stress-related diseases. The therapeutic effects and mechanism of EGCG on RIII have not yet been determined. In the present study, we investigated whether EGCG confers radioprotection against RIII. Our data demonstrated that administration of EGCG not only prolonged the survival time of lethally irradiated mice, but also reduced radiation-induced intestinal mucosal injury. Treatment with EGCG significantly increased the number of Lgr5⁺ intestinal stem cells (ISCs) and their progeny Ki67⁺ cells, and reduced radiation-induced DNA damage and apoptosis. Besides, EGCG displayed the same radioprotective effects in human intestinal epithelial HIEC cells as in mice, characterized by a decrease in the number of γH2AX foci and ferroptosis. Moreover, EGCG decreased the level of reactive oxygen species (ROS) and activated the transcription factor Nrf2 and its downstream targets comprising antioxidant proteins Slc7A11, HO-1 and GPX4. Treatment with the Nrf2 inhibitor ML385 abolished the protective effects of EGCG, indicating that Nrf2 activation is essential for EGCG activity. Taken together, our findings demonstrated that EGCG protects against RIII by scavenging ROS and inhibiting apoptosis and ferroptosis through the Nrf2 signal pathway, which could be a promising medical countermeasure for the alleviation of RIII.

Keywords: Apoptosis; EGCG; Ferroptosis; Nrf2; Radiation-induced intestinal injury; Reactive oxygen species (ROS).