8-Hydroxy-2-Anilino-1,4-Naphthoquinone Prevents Against Ferroptotic Neuronal Death and Kainate-Induced Epileptic Seizures

<b>Background/Objectives:</b> Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, has been implicated in various acute and chronic brain disorders, including epilepsy. Although 1,4-naphthoquinone derivatives have been reported to regulate ferroptosis, their mechanistic roles in the nervous system remain underexplored. Here, we investigated the protective effects of 8-hydroxy-2-anilino-1,4-naphthoquinone (8-HANQ) on ferroptotic neuronal death in vitro and seizure behaviors in vivo. <b>Methods:</b> HT22 hippocampal cells were exposed to ferroptosis inducers including glutamate, glutamate plus iron, or RSL3. Lipid reactive oxygen species (ROS), ferroptosis markers, and its related molecules were assessed by flow cytometry and Western blotting. In a kainate (KA)-induced seizure model, 8-HANQ was delivered intracerebroventricularly, followed by behavioral seizure scoring and analysis of hippocampal levels of PSD95, cathepsin-B, and FGFR1 at 72 h post-seizure. <b>Results:</b> 8-HANQ attenuated ferroptotic death in HT22 cells, reducing lipid ROS accumulation and abnormal acyl-coA synthetase long chain family member 4 (ACSL4), suggesting 8-HANQ's anti-ferroptotic action. Moreover, 8-HANQ also prevented aberrant STAT3-dependent cathepsin-B overexpression while modulating soluble N-cadherin-mediated FGFR1 activation. In vivo, 8-HANQ decreased KA-induced seizure behavior, restored hippocampal cathepsin-B and PSD95 expression, and partially alleviated dysregulation of FGFR1 activation. <b>Conclusions:</b> 8-HANQ prevents ferroptotic neuronal death and synaptic deficits involving FGFR1/STAT3/cathepsin-B-driven ferroptosis while lowering seizure severity, suggesting that 8-HANQ may serve as a potential anti-ferroptotic and anti-seizure agent.