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.