NU7441, a selective inhibitor of DNA-PKcs, alleviates intracerebral hemorrhage injury with suppression of ferroptosis in brain.

Neuronal apoptosis, oxidative stress, and ferroptosis play a crucial role in the progression of secondary brain injury following intracerebral hemorrhage (ICH). Although studies have highlighted the important functions of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in various experimental models, its precise role and mechanism in ICH remain unclear. In this study, we investigated the effects of DNA-PKcs on N2A cells under a hemin-induced hemorrhagic state in vitro and a rat model of collagenase-induced ICH in vivo . The results revealed a notable increase in DNA-PKcs levels during the acute phase of ICH. As anticipated, DNA-PKcs and γ-H2AX had consistent upregulations after ICH. Administration of NU7441, a selective inhibitor of DNA-PKcs, alleviated neurological impairment, histological damage, and ipsilateral brain edema in vivo . Mechanistically, NU7441 attenuated neuronal apoptosis both in vivo and in vitro , alleviated oxidative stress by decreasing ROS levels, and suppressed ferroptosis by enhancing GPX4 activity. These results suggest that inhibition of DNA-PKcs is a promising therapeutic target for ICH.
Competing Interests: The authors declare that they have no competing interests.
(© 2024 Gong et al.)