The role of HIF-1α/HO-1 pathway in hippocampal neuronal ferroptosis in epilepsy

Zhen Liang; Zhaoshi Zheng; Qi Guo; Meng Tian; Jing Yang; Xiu Liu; Xiaojuan Zhu; Songyan Liu

doi:10.1016/j.isci.2023.108098

The role of HIF-1α/HO-1 pathway in hippocampal neuronal ferroptosis in epilepsy

iScience. 2023 Sep 29;26(11):108098. doi: 10.1016/j.isci.2023.108098. eCollection 2023 Nov 17.

Authors

Zhen Liang^{1

2}, Zhaoshi Zheng¹, Qi Guo¹, Meng Tian², Jing Yang², Xiu Liu², Xiaojuan Zhu², Songyan Liu¹

Affiliations

¹ Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.
² Key Laboratory of Molecular Epigenetics, Ministry of Education and Institute of Cytology and Genetics, Northeast Normal University, Changchun, China.

Abstract

Epilepsy, a common central nervous system disorder, remains an enigma in pathogenesis. Emerging consensus designates hippocampal neuronal injury as a cornerstone for epileptogenic foci, pivotal in epileptic genesis and progression. Ferroptosis, a regulated cell death modality hinging on iron, catalyzes lipid reactive oxygen species formation through iron and membrane polyunsaturated fatty acid interplay, culminating in oxidative cell death. This research investigates the role of hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 in hippocampal neuron ferroptosis during epilepsy. Untargeted metabolomics exposes metabolite discrepancies between epilepsy patients and healthy individuals, unveiling escalated oxidative stress, heightened bilirubin, and augmented iron metabolism in epileptic blood. Enrichment analyses unveil active HIF-1 pathway in epileptic pathogenesis, reinforced by HIF-1α signaling perturbations in DisGeNET database. PTZ-kindled mice model confirms increased ferroptotic markers, oxidative stress, HIF-1α, and HO-1 in epilepsy. Study implicates HIF-1α/HO-1 potentially regulates hippocampal neuronal ferroptosis, iron metabolism, and oxidative stress, thereby promoting the propagation of epilepsy.

Keywords: Cell biology; Health sciences; Metabolomics; Molecular biology; Neuroscience.