The Role of Piezo 1 in the Study of Intervertebral Disc Degeneration: Phenotype, Mechanism and Treatment

ABSTRACT Background Intervertebral disc degeneration (IVDD), a prevalent spinal disorder, is closely associated with abnormal mechanical stress. The nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP) collectively respond to mechanical loading. The mechanosensitive Piezo 1 ion channel senses mechanical stress changes and converts the mechanical signals into chemical signals, and serves a pivotal role in IVDD pathogenesis. Objective This review summarizes the regional effects of Piezo 1 on mechanical stress‐induced IVDD and evaluates therapeutic strategies targeting Piezo 1 to maintain disc homeostasis. Methods A systematic search of preclinical and clinical studies was conducted to delineate Piezo 1's phenotypic impacts, mechanistic pathways, and therapeutic potential in NP, AF, and CEP. Results In the NP, activated Piezo 1 contributes to cellular senescence, apoptosis, ferroptosis, extracellular matrix (ECM) degradation and synthesis, oxidative stress, inflammation, and catabolic processes. Key regulatory targets involved include NLRP3, MAPK, p38, MMPs, ADAMTS, p65, Periostin, p53, p16, GRP78, CHOP, Cyt‐c, and Drp1. In the CEP, Piezo 1 mediates inflammation‐induced CEP degeneration through the CaMKII/Drp1 pathway and further participates in cellular senescence and apoptosis by activating Bax and caspase‐3 while inhibiting Bcl‐2. In the AF, Piezo 1 mediates apoptosis through the Ca 2+ /Calpain2/Caspase‐3 signaling pathway. Therapeutically, targeting Piezo 1 has demonstrated significant preclinical potential, including attenuating pathological alterations via pharmacological inhibition, selectively suppressing degenerative cascades through genetic/RNAi approaches, and modulating channel activity by nutritionally regulating membrane lipids. Conclusion Piezo 1 serves as a critical mechanotransducer in IVDD, exhibiting region‐specific effects on disc pathophysiology. Targeting Piezo 1 signaling not only offers mechanistic insights but also holds translational potential as a therapeutic strategy to improve IVDD, meriting further exploration in preclinical and clinical contexts.