Ezrin inhibition alleviates oxidative stress and pyroptosis via regulating TRPML1-calcineurin axis mediated enhancement of autophagy in spinal cord injury.

Abstract

Spinal cord injury (SCI) presents profound ramifications for patients, leading to diminished motor and sensory capabilities distal to the lesion site. Once SCI occurs, it not only causes great physical and psychological problems for patients but also imposes a heavy economic burden. Ezrin is involved in various cellular processes, including signal transduction, cell death, inflammation, chemotherapy resistance and the stress response. However, whether Ezrin regulates functional repair after SCI and its underlying mechanism has not been elucidated. Here, our results showed that there is a marked augmentation of Ezrin levels within neurons and Ezrin inhibition markedly diminished glial scarring and bolstered functional recuperation after SCI. RNA sequencing indicated the potential involvement of pyroptosis, oxidative stress and autophagy in the enhancement of functional recovery upon reduced Ezrin expression. Moreover, the inhibition of Ezrin expression curtailed pyroptosis and oxidative stress by amplifying autophagy. Our studies further demonstrated that Ezrin inhibition promoted autophagy by increasing TFEB activity via the Akt-TRPML1-calcineurin pathway. Finally, we concluded that inhibiting Ezrin expression alleviates pyroptosis and oxidative stress by enhancing TFEB-driven autophagy, thereby promoting functional recovery after SCI, which may be a promising therapeutic target for SCI treatment.

• Authors: Junsheng Lou, Mengran Jin, Conghui Zhou, Yunpeng Fan, Libin Ni, Yiting Mao, Honghao Shen, Jiafeng Li, Haojie Zhang, Chunyan Fu, Xingjia Mao, Yingying Chen, Jinjie Zhong, Kailiang Zhou, Linlin Wang, Junsong Wu
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 212 Pg. 133-148 (02 20 2024) ISSN: 1873-4596 [Electronic] United States
• PMID: 38142951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• ezrin
• Calcineurin
• Cytoskeletal Proteins

Topics

• Humans
• Pyroptosis
• Calcineurin (metabolism)
• Spinal Cord Injuries (drug therapy, genetics, metabolism)
• Oxidative Stress (physiology)
• Autophagy
• Cytoskeletal Proteins