A novel icariside II derivative YS-10 exerts therapeutic effects on radiation-induced testicular damage via Keap1/Nrf2/HO-1 mediated apoptosis restraint

Background Previous studies have reported that YS-10 has shown potential in ameliorating radiation-induced injury and diabetic erectile dysfunction. Nevertheless, its protective effects against radiation-induced testicular injury and the underlying mechanisms remain to be fully elucidated. Methods In this study, we aimed to explore the protective effect of YS-10 against radiation-induced testicular injury. Male Sprague-Dawley (SD) rats were subjected to a single dose of 20 Gy X-ray irradiation (2 Gy/min dose rate) to establish the in-vivo testicular radiation-injury model; GC-2 cells were exposed to a single dose of 8 Gy X-ray irradiation (2 Gy/min dose rate) to construct the in-vitro testicular radiation-injured cell model. Results YS-10 treatment elevated sperm concentration and viability in irradiated rats and ameliorated testicular inflammatory response. Functional enrichment analysis revealed that differentially expressed genes (DEGs) from testicular specimens were markedly and uniquely enriched in signaling pathways related to oxidative stress and apoptosis. Compared with the Model group, YS-10 treatment significantly suppressed Keap1 expression, facilitated Nrf2 activation and upregulated HO-1 expression. In vivo and in-vitro functional assays verified that YS-10 markedly reduced the proportion of TUNEL-positive cells, decreased intracellular ROS levels, promoted cell proliferation, rescued the collapse of mitochondrial membrane potential, upregulated anti-apoptotic Bcl-2 expression and suppressed pro-apoptotic Bax expression. Furthermore, treatment with an Nrf2 inhibitor in vitro attenuated the protective effects of YS-10. Conclusion Collectively, YS-10 significantly ameliorates radiation-induced damage in testicular tissues and GC-2 cells. Suppression of apoptosis and activation of the Keap1/Nrf2/HO-1 signaling axis are associated with the protective effects exerted by YS-10.