{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:42:53Z","timestamp":1793385773154,"version":"4.5.0"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain, characterized not only by extracellular matrix (ECM) degradation but also by a chronic low-grade inflammatory response. The crosstalk between immune microenvironment dysregulation and protease-driven ECM breakdown remains poorly understood, hindering the development of targeted therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated multiple transcriptomic datasets to map the landscape of ECM-degrading proteases in IVDD. Machine learning algorithms (LASSO, Random Forest, SVM) were employed to identify key regulatory genes. Their association with immune cell infiltration and inflammatory pathways was investigated. A diagnostic ridge regression model was constructed, and molecular docking was performed to screen for potential therapeutics. The top candidate, pravastatin sodium, was validated\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      for its effects on ECM preservation and inflammation modulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MMP3 and ADAMTS1 were identified as core genes driving ECM degradation, and their expression was strongly correlated with the abundance of pro-inflammatory immune cells and activation of inflammatory pathways. The model based on these genes effectively distinguished degenerated discs. Single-cell analysis revealed that high-degradation nucleus pulposus cells exhibited enhanced pro-inflammatory intercellular communication and metabolic reprogramming towards a pro-inflammatory state. Molecular docking confirmed high binding affinity of pravastatin sodium to MMP3 and ADAMTS1. Experimental validation demonstrated that pravastatin sodium alleviated IVDD by reducing ECM degradation, suppressing pro-inflammatory cytokine (e.g., IL-1\u03b2) expression, and inhibiting apoptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study delineates a critical network linking ECM degradation to immune microenvironment activation in IVDD, with MMP3 and ADAMTS1 serving as central hubs. Pravastatin sodium emerges as a promising therapeutic agent capable of disrupting this pathogenic network, offering a novel immunomodulatory strategy for slowing disc degeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1809762","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:35:13Z","timestamp":1776832513000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Deciphering the regulatory mechanism and therapeutic potential of ECM degradation in intervertebral disc degeneration via multi-omics integration"],"prefix":"10.3389","volume":"17","author":[{"given":"Lei","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Joint Surgery, Affiliated Hospital of Shandong Second Medical University","place":["Weifang, 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