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This study establishes PIEZO1 as a mechanosensitive ion channel central to compressive stress responses. These findings demonstrate that PIEZO1 upregulation disrupts GPX4 signaling, thereby amplifying ferroptosis in vertebral growth plate chondrocytes and accelerating pathological ossification. Pharmacological inhibition of PIEZO1 effectively attenuated iron overload, mitigated oxidative stress, and suppressed mechanical stress\u2010induced ferroptosis cascades. Notably, both conditional PIEZO1 knockout models (Col2a1\u2010CreERT; Piezo1\n                    <jats:sup>flox\/flox<\/jats:sup>\n                    ) and pharmacological blockade significantly decelerate scoliosis progression. However, osteoporosis emerges as an unintended consequence of systemic PIEZO1 inhibition, likely attributable to its essential role in osteogenic differentiation. To overcome this limitation, a targeted therapeutic strategy employing micro endoscopy\u2010guided hydrogel\u2010mediated delivery of PIEZO1 inhibitors is developed, achieving spatially restricted modulation within vertebral growth plate cartilage. These results position PIEZO1 as a pivotal regulator of VGPD progression through its coordination of the PIEZO1\u2010GPX4\u2010ferroptosis axis. This work not only elucidates a novel mechanobiological pathway underlying growth plate degeneration but also introduces a precision drug delivery platform with translational potential for VGPD management. The micro\u2010endoscopy\u2010assisted hydrogel system represents a paradigm shift in localized treatment of skeletal disorders while circumventing systemic complications.\n                  <\/jats:p>","DOI":"10.1002\/advs.202502052","type":"journal-article","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T13:51:17Z","timestamp":1753537877000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["PIEZO1\u2010GPX4 Axis Mediates Mechanical Stress\u2010Induced Vertebral Growth Plate Dysplasia via Ferroptosis Activation"],"prefix":"10.1002","volume":"12","author":[{"given":"Fei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Spinal Surgery The Affiliated Hospital of Qingdao University  Qingdao Shandong 266071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fushuai","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Spinal Surgery The 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