2. Academic Validation
  3. Targeting EGR1-ATF3 signaling mitigates paravertebral muscle degeneration by regulating cell death and inflammaging

Targeting EGR1-ATF3 signaling mitigates paravertebral muscle degeneration by regulating cell death and inflammaging

  • Biol Res. 2025 Jul 28;58(1):52. doi: 10.1186/s40659-025-00634-1.
Xuke Wang # 1 2,  Qingfeng Wang # 2,  Zhe Wang 2,  Yingjie Zhou 3,  Xiaobing Jiang 4,  Yongjin Li 5 6
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou City, Guangdong Province, 510405, China.
  • 2 Department of Minimally Invasive Spine Surgery, Luoyang Orthopedic Hospital of Henan Province. Orthopedic Hospital of Henan Province, 82 Qiming South Road, Luoyang City, Henan Province, 471000, China.
  • 3 Department of Minimally Invasive Spine Surgery, Luoyang Orthopedic Hospital of Henan Province. Orthopedic Hospital of Henan Province, 82 Qiming South Road, Luoyang City, Henan Province, 471000, China. 1099168230@qq.com.
  • 4 Department of Orthopaedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou City, Guangdong Province, 510405, China. spinedrjxb@sina.com.
  • 5 Spine Center, Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No.17, Lujiang Road, Hefei City, Anhui Province, 230001, China. yongjin816@ustc.edu.cn.
  • 6 Department of Orthopedics, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xicheng District, Beijing City, 230012, China. yongjin816@ustc.edu.cn.
  • # Contributed equally.
PMID: 40722201 DOI: 10.1186/s40659-025-00634-1
Abstract

The paravertebral muscles play a critical role in maintaining dynamic spinal stability and physiological function. With aging, these muscles undergo senescence and degeneration, contributing to spinal instability and the development of low back pain. Age-related cellular death further accelerates chronic, low-grade inflammation termed “inflammaging” and disrupts the extracellular matrix (ECM), representing a key pathogenic mechanism driving paravertebral muscle degeneration (PMD). However, the core regulatory genes orchestrating inflammaging in this context have yet to be fully elucidated. The paravertebral muscles play an important role in supporting dynamic stability and physiological function of the spine. This study identified 409 differentially expressed genes (DEGs) through RNA Sequencing. Subsequent bioinformatics analysis revealed 81 functionally relevant DEGs, with several hub genes such as Activating Transcription Factor 3 (ATF3), Cyclin-Dependent Kinase Inhibitor 1 A (CDKN1A/p21), and Interleukin-6 (IL-6) being significantly upregulated. These genes are associated with cellular death, ECM metabolic dysregulation, and inflammaging. Functional experiments demonstrated that silencing ATF3 attenuated cellular death, reduced inflammatory signaling, and preserved ECM integrity by modulating downstream effectors including CDKN1A/p21, IL6, Gasdermin E (GSDME), and Glutathione Peroxidase 4 (GPX4). Further network analysis identified the Early Growth Response 1 (EGR1)–ATF3 signaling axis, with EGR1 knockdown protecting against PMD through downregulation of ATF3. These genes may also exhibit high specificity and sensitivity for distinguishing PMD, suggesting their potential utility as diagnostic biomarkers. Overall, this study provides new insights into the molecular mechanisms underlying PMD and offers promising targets for therapeutic intervention.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40659-025-00634-1.

Keywords

Cell death; EGR1-ATF3 signaling; Inflammaging; Paravertebral muscle degeneration; RNA sequencing.

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