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

Abstract

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.