{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:02:00Z","timestamp":1790146920930,"version":"4.0.1"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"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. Cell Dev. Biol."],"abstract":"<jats:p>\n                    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-\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"m1\">\n                        <mml:mrow>\n                          <mml:mi>\u03ba<\/mml:mi>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    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\u2013NF-\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"m2\">\n                        <mml:mrow>\n                          <mml:mi>\u03ba<\/mml:mi>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1938559","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:20:58Z","timestamp":1790144458000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Iron, lipid peroxidation and discogenic pain: a redox framework for ferroptosis in intervertebral disc degeneration"],"prefix":"10.3389","volume":"14","author":[{"given":"Qiyun","family":"Shi","sequence":"first","affiliation":[{"name":"Luoyang Orthopedic-Traumatological Hospital of Henan Province (Henan Provincial Orthopedic Hospital)","place":["Luoyang, China"]},{"name":"Massey University","place":["Auckland, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Xu","sequence":"additional","affiliation":[{"name":"Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Zhai","sequence":"additional","affiliation":[{"name":"Luoyang Orthopedic-Traumatological Hospital of Henan Province (Henan Provincial Orthopedic Hospital)","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitian","family":"Li","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration","place":["Xinxiang, China"]},{"name":"Zhongyuan Regenerative Medicine Laboratory","place":["Xinxiang, China"]},{"name":"Xinxiang Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongwei","family":"Song","sequence":"additional","affiliation":[{"name":"Luoyang Orthopedic-Traumatological Hospital of Henan Province (Henan Provincial Orthopedic Hospital)","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1080\/10715762.2018.1468564","article-title":"N-acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why","volume":"52","author":"Aldini","year":"2018","journal-title":"Free Radic. 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