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Discogenic low back pain, the most common type of low back pain, is closely related to cartilage endplate (CEP) degeneration and inflammation. In this study, by constructing a rat model of lumbar spine instability (LSI) and combining biomechanical analysis with molecular biology techniques, we revealed the central role of the mechanosensitive channel Piezo2 in the vicious cycle of discogenic low back pain. The results revealed that abnormal mechanical stress triggers calcium influx and promotes CGRP release by activating Piezo2 in the dorsal root ganglion (DRG). CGRP synergizes with mechanical force to activate the IKK\u03b2\/NF\u2010\u03baB pathway in CEP cells via the receptor RAMP1, which induces the secretion of IL\u20106 and IL\u20101\u03b2, and further sensitizes DRG neurons, forming a positive feedback loop. Macrophage depletion did not alleviate pain\/inflammation. Targeted inhibition of Piezo2 (with AAV\u2010shPiezo2 gene silencing or omega\u20103 fatty acids) or blockade of CGRP signaling (with Rimegepant) significantly alleviated pain\u2010related behaviors, suppressed inflammation, and delayed CEP degeneration. This study elucidated a novel mechanism by which mechanical\u2012neuroinflammatory interactions drive the progression of discogenic low back pain and provided a theoretical basis for the development of multitargeted combination treatment strategies.<\/jats:p>","DOI":"10.1002\/advs.202507299","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T19:30:41Z","timestamp":1776367841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Piezo2 Mediates a Vicious Cycle of \u201cMechanical Homeostasis Imbalance\u2014Inflammation\u201d in Sensory Nerves and the Cartilage Endplate"],"prefix":"10.1002","volume":"13","author":[{"given":"Hanpeng","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 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