The ferroptosis-mediated domino effect: metabolic crosstalk from intervertebral disc degeneration to spinal deformity and cord injury: a mini review

Spinal degeneration, spinal deformity, and spinal cord injury (SCI) are classically managed as discrete biomechanical or neurological entities. However, emerging evidence reveals them as an interconnected pathological continuum. This mini-review introduces the “ferroptosis-mediated domino effect” as the core metabolic driver linking these conditions. The cascade initiates within the avascular intervertebral disc, where aberrant mechanotransduction (e.g., via Piezo1) provokes severe oxidative stress and subsequent ferroptosis, leading to extracellular matrix degradation and structural collapse. The ensuing spinal deformity chronically compresses the spinal microvasculature, disrupting the blood-spinal cord barrier (BSCB) and facilitating localized iron deposition. This chronic ischemic insult generates a metabolically “primed” spinal cord characterized by extreme vulnerability. Upon secondary acute trauma, the sudden influx of heme and labile iron ignites an uncontrollable “ferroptotic storm,” synergizing with neuroinflammation to drive irreversible neural loss. Finally, we evaluate cutting-edge translational interventions, including reactive oxygen species (ROS)-responsive nanoparticles and nanozyme-loaded hydrogels, that offer spatiotemporal precision to halt this pathological crosstalk. By dismantling disciplinary silos, this framework advocates for next-generation, dual-action therapeutic strategies that simultaneously restore biomechanical stability and mitigate metabolic collapse.