p23 protects against ferroptosis of brain microvascular endothelial cells in ischemic stroke

Zhao,Yao; Xu,Yunfei; Xu,Qing; He,Nina; Zhao,Jie; Liu,Ying

doi:10.3892/ijmm.2025.5505

p23 protects against ferroptosis of brain microvascular endothelial cells in ischemic stroke

Authors:
- Yao Zhao
- Yunfei Xu
- Qing Xu
- Nina He
- Jie Zhao
- Ying Liu
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Affiliations: Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: February 19, 2025 https://doi.org/10.3892/ijmm.2025.5505
Article Number: 64
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ferroptosis is a type of iron‑dependent regulated cell death that differs from apoptosis, autophagy or necrosis. p23 serves as a co‑chaperone and performs a unique biological function in various diseases by binding to client proteins to modulate their biological functions; however, its effect on ferroptosis remains largely unknown. In the present study, the effects of cerebral ischemia/reperfusion (I/R) injury (CIRI) or oxygen‑glucose deprivation/reoxygenation on the blood‑brain barrier (BBB) and ferroptosis in brain microvascular endothelial cells (BMECs), as well as the expression of p23, were examined. Subsequently, the effects of p23 on CIRI‑induced BBB dysfunction and BMEC ferroptosis were determined. Finally, the role of glutathione peroxidase 4 (GPX4) in the regulatory effects of p23 on ferroptosis was detected. The results revealed that p23 protected against BBB injury caused by CIRI by inhibiting ferroptosis in BMECs. The effect of p23 on ferroptosis was then explored, and it was found that the expression of GPX4, a major regulator of ferroptosis, was promoted by p23. Furthermore, molecular docking and co‑immunoprecipitation experiments revealed that p23 could bind to GPX4 through its N‑terminal domain (1‑90aa), enhance the stability of GPX4 and inhibit the degradation of GPX4 by cycloheximide. Finally, a cerebral I/R animal model was established using GPX4 conditional knockout mice (GPX4 Fos^CreERT2/+), and it was revealed that the protective effect of p23 overexpression on the BBB in GPX4 Fos^CreERT2/+ mice was attenuated compared with that in GPX4 Fos^CreERT2/‑ mice. In conclusion, p23 may serve a protective role against cerebral I/R‑induced BBB injury by inhibiting ferroptosis in BMECs through enhancing the stability of GPX4, providing a potential therapeutic target for ischemic stroke.

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