Metformin is one of the most effective therapies for treating type 2 diabetes and has been shown to also attenuate aging and age-related disorders. In this study, we explored the relationship between metformin and DNA damage repair in ionizing radiation (IR)-induced damage of human aortic endothelial cells (HAECs). Metformin treatment suppressed IR-induced senescence phenotypes, such as increased senescent-associated β-galactosidase (SA β-gal) activity and decreased tube formation and proliferation. Moreover, metformin increased BRCA1-associated RING domain protein 1 (BARD1) and RAD51 expression in both aging and IR-exposed cells. Metformin-treated cells exhibited higher levels of the BRCA1-BARD1-RAD51 complex during irradiation, even in the presence of compound C, an AMP-activated protein kinase inhibitor. BARD1 knockdown confirmed its critical role in metformin-mediated inhibition of endothelial senescence. Metformin increased blood vessel sprouting and decreased SA β-gal activity in mouse aortas. Collectively, our findings provide new insights into how metformin can prevent endothelial cell senescence by promoting BARD1-related DNA damage repair, suggesting that metformin may be an effective anti-aging agent and a promising therapeutic for protecting against radiation-induced cardiotoxicity.

Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.

Current studies have elucidated the mechanisms of radiation-induced skin injury (RISI) and identified several medical countermeasures to reduce its severity. However, no treatment has yet proven effective in preventing or reversing radiation-induced skin fibrosis. Here, we show that radiation upregulates lipoprotein-associated phospholipase A2 (Lp-PLA₂) expression and induces endothelial cell dysfunction, characterized by an increased DNA damage response and reduced tube-forming capacity and mitochondrial function. To define the role of Lp-PLA₂ in the progression of RISI, we treated human dermal microvascular endothelial cells and the skin of SKH1 hairless mice with darapladib, a selective Lp-PLA₂ inhibitor. In endothelial cells, darapladib attenuated radiation-induced cellular damage and suppressed endothelial-to-mesenchymal transition (EndoMT). In irradiated mouse skin, darapladib reduced radiation-induced inflammation, adipose tissue disruption, dermal thickness, and skin fibrosis. Notably, darapladib modulated macrophage polarization and inhibited radiation-induced macrophage infiltration in irradiated skin. These findings suggest that Lp-PLA₂ inhibition may reveal potential targets for the treatment of RISI and other fibrotic skin diseases.