Ferroptosis in Intervertebral Disc Degeneration: How the Extreme Microenvironment Rewires a Cell Death Network

Ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation, contributes to intervertebral disc degeneration (IVDD), yet most reviews describe its pathways without asking why the disc-the largest avascular tissue, combining hypoxia, nutrient deprivation, mechanical loading, acidosis, and low-grade inflammation-regulates ferroptosis differently from other tissues. Here we address this question along three axes. First, the execution machinery shows three IVDD-specific vulnerabilities: a proposed diffusion-limited cystine "semi-starvation", mechanically induced GPX4 inhibition via the Piezo1-Ca²⁺ axis, and epigenetic GCLC suppression. Second, iron homeostasis undergoes a "triangular imbalance": TFR1 upregulation coexists with restricted iron supply, acidosis-activated NCOA4 ferritinophagy is proposed as the dominant source of labile iron (with the UCHL3-HMGB1-NCOA4 axis as a newly identified upstream regulator), and FPN1 export is blocked by the IL-6-hepcidin axis, predisposing Nrf2-HO-1 to a protective-to-deleterious functional reversal. Third, inflammation and ferroptosis form a vicious cycle in which STAT3 signals through the non-canonical S100A6-p53 axis-opposite to its tumour-protective FTH1 role-jointly imposing a "dual lock" on SLC7A11. Integrating these findings, we construct a network in which Nrf2 is proposed as the transcriptional hub and SLC7A11 as the convergent bottleneck, and derive an SLC7A11-restoration hypothesis predicting that multi-target combinations, not single-pathway interventions, will be required-a prediction that remains to be tested. We close by discussing the controversies and a prioritized research agenda.