PIEZO1‐GPX4 Axis Mediates Mechanical Stress‐Induced Vertebral Growth Plate Dysplasia via Ferroptosis Activation

Abstract Current scientific consensus acknowledges mechanical stress, particularly compressive loading, as a critical contributor to the pathogenesis of vertebral growth plate disorders (VGPD), though the precise molecular mechanisms remain incompletely understood. 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‐induced ferroptosis cascades. Notably, both conditional PIEZO1 knockout models (Col2a1‐CreERT; Piezo1 flox/flox ) 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‐guided hydrogel‐mediated 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‐GPX4‐ferroptosis 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‐endoscopy‐assisted hydrogel system represents a paradigm shift in localized treatment of skeletal disorders while circumventing systemic complications.