PIEZO1 impairs antioxidant capacity and drives ferroptosis via dual regulation of GPX4 in degenerative disc cells

Intervertebral disc degeneration (IVDD) constitutes the leading cause of chronic low back pain. Oxidative stress and ferroptosis act as critical pathological drivers of IVDD progression. Nevertheless, the cellular heterogeneity of nucleus pulposus cells (NPCs), endogenous repair homeostasis, and the regulatory network linking mechanical signals to ferroptosis remain poorly defined. In the present study, single-cell RNA sequencing was adopted to dissect the dynamic features of human NPC subpopulations, verifying that progressive depletion of progenitor NPCs (P-NPCs) serves as the core trigger for disrupted repair homeostasis during IVDD development. Combined with clinical specimen validation, multi-omics profiling and in vitro cellular models, we demonstrated that aberrant mechanical stress activates the mechanosensitive ion channel PIEZO1 and triggers Ca²⁺ influx. This event downregulates the transcription of GPX4, the master effector against ferroptosis; simultaneously, it upregulates the E3 ubiquitin ligase TRIM21 to accelerate GPX4 ubiquitination and subsequent proteasomal degradation. These two coordinated pathways aggravate oxidative stress, iron overload and lipid peroxidation in NPCs, accompanied by typical mitochondrial morphological damage. Ferroptotic NPCs further shape a pathological microenvironment that suppresses P-NPC viability and triggers P-NPC apoptosis, thereby establishing a cascading and self-amplifying degenerative loop. Both in vitro treatment with a PIEZO1 inhibitor and in vivo mechanical loading assays using nucleus pulposus-specific PIEZO1 knockout mice validated that PIEZO1 blockade restores GPX4 activity, rebalances redox homeostasis and robustly retards IVDD progression.