Mechanistic Interactions Driving Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration: A Multi‐Axial Perspective of Mechanical, Immune, and Metabolic Pathways

ABSTRACT Background 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 2+ overload by activating the Piezo‐type mechanosensitive ion channel component 1 (PIEZO1) channel. Aims This creates a positive feedback loop of oxidative‐inflammatory damage by inducing endoplasmic reticulum stress and mitochondrial reactive oxygen species (ROS) bursts, as well as directly activating the NLRP3 inflammasome/NF‐кB axis to promote the release of pro‐inflammatory factors like IL‐1β. Results Energy metabolism collapsed as a result of mechanistic cause that caused excessive activation of mitophagy via the ROS‐PINK1/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‐α/IL‐1β 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‐induced ATM/ATR kinase activation leads to p53 phosphorylation, which triggers p21‐mediated cell‐cycle block. On the other hand, p53 exacerbates mitochondrial dysfunction by inhibiting SIRT1 expression, creating a triangular amplification loop of p53‐ROS‐mitophagy. Furthermore, p53 stimulates apoptosis by altering the Bax/Bcl‐2 balance and works in concert with inflammatory substances secreted by M1‐type macrophages to cause the development of senescence‐associated secretory phenotype (SASP). Conclusion This interaction network reveals the dynamic coupling of mechano‐immune‐metabolic pathways in the course of IVDD, providing a theoretical basis for the development of multi‐targeted intervention strategies, such as PIEZO1 inhibitors combined with M2‐type macrophage polarization modulation, which are expected to delay disease progression by blocking key nodes.