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 <i>in vitro</i> and a rat model of collagenase-induced ICH <i>in vivo</i>. 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 <i>in vivo</i>. Mechanistically, NU7441 attenuated neuronal apoptosis both <i>in vivo</i> and <i>in vitro</i>, 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.