靶向EGR1-ATF3信号通路可通过调节细胞死亡和炎症衰老来减轻椎旁肌退变。

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

作者信息

Wang Xuke, Wang Qingfeng, Wang Zhe, Zhou Yingjie, Jiang Xiaobing, Li Yongjin

机构信息

Department of Orthopaedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou City, Guangdong Province, 510405, China.

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.

出版信息

Biol Res. 2025 Jul 28;58(1):52. doi: 10.1186/s40659-025-00634-1.

DOI:10.1186/s40659-025-00634-1

PMID:40722201

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12302741/

Abstract

UNLABELLED

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.

摘要

未标注

椎旁肌在维持脊柱动态稳定性和生理功能方面发挥着关键作用。随着年龄增长，这些肌肉会发生衰老和退化，导致脊柱不稳定和下腰痛的发生。与年龄相关的细胞死亡进一步加速了称为“炎症衰老”的慢性低度炎症，并破坏细胞外基质（ECM），这是驱动椎旁肌退变（PMD）的关键致病机制。然而，在这种情况下协调炎症衰老的核心调控基因尚未完全阐明。椎旁肌在支持脊柱的动态稳定性和生理功能方面发挥着重要作用。本研究通过RNA测序鉴定出409个差异表达基因（DEG）。随后的生物信息学分析揭示了81个功能相关的DEG，其中一些枢纽基因如激活转录因子3（ATF3）、细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A/p21）和白细胞介素-6（IL-6）显著上调。这些基因与细胞死亡、ECM代谢失调和炎症衰老有关。功能实验表明，沉默ATF3可减轻细胞死亡、减少炎症信号，并通过调节包括CDKN1A/p21、IL6、Gasdermin E（GSDME）和谷胱甘肽过氧化物酶4（GPX4）在内的下游效应器来维持ECM完整性。进一步的网络分析确定了早期生长反应1（EGR1）-ATF3信号轴，EGR1基因敲低通过下调ATF3来预防PMD。这些基因在区分PMD方面也可能表现出高特异性和敏感性，表明它们作为诊断生物标志物的潜在用途。总体而言，本研究为PMD的分子机制提供了新见解，并为治疗干预提供了有前景的靶点。