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

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

  • Free Radic Biol Med. 2023 Dec 22:S0891-5849(23)01176-0. doi: 10.1016/j.freeradbiomed.2023.12.020.
Junsheng Lou 1,  Mengran Jin 1,  Conghui Zhou 1,  Yunpeng Fan 1,  Libin Ni 2,  Yiting Mao 3,  Honghao Shen 1,  Jiafeng Li 1,  Haojie Zhang 4,  Chunyan Fu 5,  Xingjia Mao 5,  Yingying Chen 6,  Jinjie Zhong 6,  Kailiang Zhou 7,  Linlin Wang 8,  Junsong Wu 9
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China.
  • 2 Department of Orthopaedics, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, No. 1229 Gudun Road, Hangzhou, 310030, Zhejiang, China.
  • 3 Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
  • 4 Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China.
  • 5 Department of Basic Medicine Sciences, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 6 Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. Electronic address: zhoukailiang@wmu.edu.cn.
  • 8 Department of Basic Medicine Sciences, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Tarim University, School of Medicine, Alar, 843300, China. Electronic address: wanglinlin@zju.edu.cn.
  • 9 Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China. Electronic address: wjs1288@zju.edu.cn.
PMID: 38142951 DOI: 10.1016/j.freeradbiomed.2023.12.020
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.

Keywords

Autophagy; Ezrin; Oxidative stress; Pyroptosis; Spinal cord injury; TFEB.

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