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Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52

Authors :
Shengyou Li
Xue Gao
Yi Zheng
Yujie Yang
Jianbo Gao
Dan Geng
Lingli Guo
Teng Ma
Yiming Hao
Bin Wei
Liangliang Huang
Yitao Wei
Bing Xia
Zhuojing Luo
Jinghui Huang
Source :
Journal of Pharmaceutical Analysis, Vol 14, Iss 1, Pp 86-99 (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Details

Language :
English
ISSN :
20951779
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Journal of Pharmaceutical Analysis
Publication Type :
Academic Journal
Accession number :
edsdoj.998fca78f1d4e79a6f26a589963a15c
Document Type :
article
Full Text :
https://doi.org/10.1016/j.jpha.2023.08.006