{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:45:14Z","timestamp":1792723514686,"version":"4.5.0"},"reference-count":52,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JOR Spine"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The senescence of nucleus pulposus cells (NPCs) at the heart of the pathogenesis of intervertebral disc degeneration (IVDD), which causes low back pain. Abnormal mechanical stress causes intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      overload by activating the Piezo\u2010type mechanosensitive ion channel component 1 (PIEZO1) channel.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This creates a positive feedback loop of oxidative\u2010inflammatory damage by inducing endoplasmic reticulum stress and mitochondrial reactive oxygen species (ROS) bursts, as well as directly activating the NLRP3 inflammasome\/NF\u2010\u043aB axis to promote the release of pro\u2010inflammatory factors like IL\u20101\u03b2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Energy metabolism collapsed as a result of mechanistic cause that caused excessive activation of mitophagy via the ROS\u2010PINK1\/Parkin pathway, and SIRT1 functional suppression further compromised mitochondrial quality control. The inflammatory nucleus pulposus (NP) brought on by mechanical stimulation caused macrophages to polarize toward the M1 type, and the p38MAPK pathway was activated by the TNF\u2010\u03b1\/IL\u20101\u03b2 released, which in turn increased senescence markers like p16\/p21. Notably, ROS both triggers mitophagy and activates the p53 pathway. On the one hand, oxidative damage\u2010induced ATM\/ATR kinase activation leads to p53 phosphorylation, which triggers p21\u2010mediated cell\u2010cycle block. On the other hand, p53 exacerbates mitochondrial dysfunction by inhibiting SIRT1 expression, creating a triangular amplification loop of p53\u2010ROS\u2010mitophagy. Furthermore, p53 stimulates apoptosis by altering the Bax\/Bcl\u20102 balance and works in concert with inflammatory substances secreted by M1\u2010type macrophages to cause the development of senescence\u2010associated secretory phenotype (SASP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This interaction network reveals the dynamic coupling of mechano\u2010immune\u2010metabolic pathways in the course of IVDD, providing a theoretical basis for the development of multi\u2010targeted intervention strategies, such as PIEZO1 inhibitors combined with M2\u2010type macrophage polarization modulation, which are expected to delay disease progression by blocking key nodes.<\/jats:p>\n                  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