GPX4 activator enhances neuroprotection and functional recovery in spinal cord injury

Xinjie Liu; Yilin Pang; Baoyou Fan; Jiawei Zhang; Shen Liu; Xiaobing Deng; Yun Li; Ying Liu; Xu Zhang; Chenxi Zhao; Xiaoyu Wang; Xudong Wu; Luhua Lai; Shiqing Feng; Wenpeng Liu; Guangzhi Ning; Xue Yao

doi:10.1016/j.jot.2025.03.013

Journal of Orthopaedic Translation (May 2025)

GPX4 activator enhances neuroprotection and functional recovery in spinal cord injury

Xinjie Liu,
Yilin Pang,
Baoyou Fan,
Jiawei Zhang,
Shen Liu,
Xiaobing Deng,
Yun Li,
Ying Liu,
Xu Zhang,
Chenxi Zhao,
Xiaoyu Wang,
Xudong Wu,
Luhua Lai,
Shiqing Feng,
Wenpeng Liu,
Guangzhi Ning,
Xue Yao

Affiliations

Xinjie Liu: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China
Yilin Pang: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China
Baoyou Fan: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China
Jiawei Zhang: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China
Shen Liu: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China
Xiaobing Deng: College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
Yun Li: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China
Ying Liu: College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
Xu Zhang: Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Center for Cardiovascular Diseases, Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
Chenxi Zhao: Department of Orthopedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopedics, Advanced Medical Research Institute, Shandong University, Jinan, Shandong, 250012, China
Xiaoyu Wang: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China
Xudong Wu: Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
Luhua Lai: College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
Shiqing Feng: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China; Department of Orthopedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopedics, Advanced Medical Research Institute, Shandong University, Jinan, Shandong, 250012, China
Wenpeng Liu: Renal Division and Division of Engineering in Medicine, Department of Medicine, Brigham Women's Hospital, Harvard Medical School, Harvard University, Boston, MA, 02115, USA; Corresponding author.
Guangzhi Ning: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China; Corresponding author.
Xue Yao: Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China; Department of Orthopedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopedics, Advanced Medical Research Institute, Shandong University, Jinan, Shandong, 250012, China; Corresponding author. Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China.

DOI: https://doi.org/10.1016/j.jot.2025.03.013
Journal volume & issue: Vol. 52
pp. 344 – 359

Abstract

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Background: Spinal cord injury (SCI) exerts severe physical, social, and economic effects on individuals and the healthcare system. While much progress has been made in understanding the pathophysiology of SCI, the regulation of the ferroptosis master regulator, GPX4 (Glutathione Peroxidase 4), remains poorly understood. Methods: In a rat T10 contusion SCI model, GPX4 expression was tracked with western blot and immunofluorescence. Ferroptosis was induced in primary neurons using the GPX4 inhibitor RSL3, and inflammatory cytokine release was measured. Conditioned media from these neurons was applied to microglia to assess activation. The GPX4 activator PKUMDL-LC-102 was administered to SCI rats, with functional recovery evaluated through behavioral tests, MRI, and motor-evoked potentials. Results: We first reveal a temporal and spatial decrease of GPX4 levels in neurons after SCI. We then demonstrate that GPX4 inhibition leads to primary neuronal ferroptosis, triggering the secretion of pro-inflammatory cytokines that activate microglia. This study represents the initial in vivo investigation of GPX4-specific targeted activation, demonstrating its potential to promote functional recovery in contusive SCI by improving neuronal survival and reducing microgliosis. Conclusion: These findings highlight the significance of GPX4 as a key factor for neuroprotection in the spinal cord. We identified the pivotal role of GPX4 in SCI and realize the neuroprotection via specific GPX4 activation to improve functional recovery in vivo. The translational potential of this article: These findings provide a novel avenue for therapeutic intervention to enhance functional recovery after SCI through GPX4 targeted activation.

Published in Journal of Orthopaedic Translation

ISSN: 2214-031X (Print); 2214-0328 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the musculoskeletal system
Website: https://www.sciencedirect.com/journal/journal-of-orthopaedic-translation

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