{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:54:52Z","timestamp":1781848492212,"version":"3.54.5"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>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 \u201cferroptosis-mediated domino effect\u201d 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 \u201cprimed\u201d spinal cord characterized by extreme vulnerability. Upon secondary acute trauma, the sudden influx of heme and labile iron ignites an uncontrollable \u201cferroptotic storm,\u201d synergizing with neuroinflammation to drive irreversible neural loss. Finally, we evaluate cutting-edge translational interventions\u2014including reactive oxygen species (ROS)-responsive nanoparticles and nanozyme-loaded hydrogels\u2014that 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.<\/jats:p>","DOI":"10.3389\/fnins.2026.1855414","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:48:08Z","timestamp":1781848088000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The ferroptosis-mediated domino effect: metabolic crosstalk from intervertebral disc degeneration to spinal deformity and cord injury: a mini review"],"prefix":"10.3389","volume":"20","author":[{"given":"ZhiYu","family":"Zhang","sequence":"first","affiliation":[{"name":"Hospital of Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YiBo","family":"Dong","sequence":"additional","affiliation":[{"name":"Chongqing Orthopedic Hospital of Traditional Chinese Medicine","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yu","sequence":"additional","affiliation":[{"name":"Hospital of Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiaoHong","family":"Fan","sequence":"additional","affiliation":[{"name":"Hospital of Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1097\/CORR.0000000000000712","article-title":"Development and characterization of a novel bipedal standing mouse model of intervertebral disc and facet joint degeneration","volume":"477","author":"Ao","year":"2019","journal-title":"Clin. 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Res."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/s12951-026-04114-w","article-title":"A dual-action nanoparticle approach for spinal cord injury treatment: ferroptosis inhibition, inflammation control, and myelin preservation","volume":"24","author":"Xue","year":"2026","journal-title":"J. Nanobiotechnol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.4103\/NRR.NRR-D-23-01848","article-title":"Nanoparticles for the treatment of spinal cord injury","volume":"20","author":"Yang","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"578","DOI":"10.2176\/nmc.oa.2015-0022","article-title":"Inflammation level after decompression surgery for a rat model of chronic severe spinal cord compression and effects on ischemia-reperfusion injury","volume":"55","author":"Yang","year":"2015","journal-title":"Neurol. Med. Chir. 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Biol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1002\/ame2.12485","article-title":"Ischemia-reperfusion injury after spinal cord decompressive surgery-an in vivo rat model","volume":"8","author":"Zhang","year":"2025","journal-title":"Anim. Model Exp. Med."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s12974-026-03760-z","article-title":"OSBPL10 alleviates neuronal ferroptosis via lysosomal membrane repair in a PS-dependent manner after spinal cord injury","volume":"23","author":"Zhang","year":"2026","journal-title":"J. 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