Iron, lipid peroxidation and discogenic pain: a redox framework for ferroptosis in intervertebral disc degeneration

The weak correlation between radiographic disc degeneration and pain intensity remains unresolved in intervertebral disc degeneration (IVDD). This Review proposes that iron-dependent lipid peroxidation and ferroptosis-associated redox signalling constitute an underrecognised link between degenerative stress and a pro-nociceptive disc microenvironment. Two linked frameworks are developed. The pro-ferroptotic niche integrates four disc-specific mechanisms: Piezo1-mediated iron influx, ferroportin suppression, ferritinophagy mediated by the cargo receptor NCOA4, and glycolysis-derived lactate upregulating the PUFA-activating enzyme ACSL4. ALOX15-coupled lipid peroxidation rests mainly on cross-disease inference. The ferroptotic pain hub proposes that resulting damage-associated signals, including the alarmin HMGB1 and 4-hydroxynonenal, may converge on NF- $\kappa$ B-dependent induction of NGF, BDNF, and IL-6. Relevant receptor-level signalling is supported in disc cells, whereas the ferroptosis-specific coupling remains untested. Intervention is organised into four tiers: iron handling, antioxidant-reserve restoration, lipid-peroxidation blockade, and damage-signal-NF- $\kappa$ B interruption. Deferoxamine and N-acetylcysteine are discussed as an illustrative, unvalidated multi-tier combination, with translation constrained by the need for disc-adapted delivery, intradiscal pharmacokinetic/pharmacodynamic characterisation, local safety assessment, and pain-endpoint validation. Disc-specific evidence, cross-disease inference, mechanistic inference, and hypothesis-level prediction are distinguished throughout, with falsifiable tests defined. The aim is not to present ferroptosis as a proven cause of discogenic pain, but to offer a testable framework for mechanism-based stratification of painful IVDD.