Radiotherapy is an essential treatment for endometrial cancer (EC), especially in advanced, metastatic, and recurrent cases. Combining radiotherapy, which mainly causes DNA double-strand breaks (DSBs), with small molecules targeting aberrantly activated homologous recombination (HR) repair pathways holds great potential for treating ECs in advanced stages. Here, we demonstrate that diosmetin (DIO), a natural flavonoid, suppresses HR, therefore inhibiting cell proliferation and enhancing the sensitivity of EC to radiotherapy. Clonogenic experiments revealed that combining DIO and X-ray significantly inhibited the viability of EC cells compared to cells treated with diosmetin or X-ray alone. The survival fraction of EC cells decreased to 40% when combining 0.4 Gy X-ray and 4 μM DIO; however, each treatment alone only caused death in approximately 15% and 22% of cancer cells, respectively. Further mechanistic studies showed that diosmetin inhibited the recruitment of RPA2 and RAD51, two critical factors involved in the HR repair pathway, upon the occurrence of DSBs. Thus, we propose that a combination of diosmetin and irradiation is a promising therapeutic strategy for treating endometrial cancer.

Radiotherapy is an essential treatment for endometrial cancer (EC), especially in advanced, metastatic, and recurrent cases. Combining radiotherapy, which mainly causes DNA double-strand breaks (DSBs), with small molecules targeting aberrantly activated homologous recombination (HR) repair pathways holds great potential for treating ECs in advanced stages. Here, we demonstrate that diosmetin (DIO), a natural flavonoid, suppresses HR, therefore inhibiting cell proliferation and enhancing the sensitivity of EC to radiotherapy. Clonogenic experiments revealed that combining DIO and X-ray significantly inhibited the viability of EC cells compared to cells treated with diosmetin or X-ray alone. The survival fraction of EC cells decreased to 40% when combining 0.4 Gy X-ray and 4 μM DIO; however, each treatment alone only caused death in approximately 15% and 22% of cancer cells, respectively. Further mechanistic studies showed that diosmetin inhibited the recruitment of RPA2 and RAD51, two critical factors involved in the HR repair pathway, upon the occurrence of DSBs. Thus, we propose that a combination of diosmetin and irradiation is a promising therapeutic strategy for treating endometrial cancer.