{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T07:03:08Z","timestamp":1782975788789,"version":"3.54.5"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"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>Intervertebral disc degeneration (IVDD) is commonly framed as the cumulative result of extracellular matrix loss, inflammatory activation, oxidative damage, cellular senescence and cell death. This formulation is useful, but it also fragments the disease into parallel mechanisms and obscures a central paradox: nucleus pulposus and annulus fibrosus cells normally reside in a microenvironment that would be hostile to most mammalian cells. The healthy disc is avascular, diffusion limited, hypoxic, glycolytic, relatively acidic and mechanically loaded. These features are not simply pathological insults; they are defining ecological constraints to which disc cells are continuously adapted. Here we propose that IVDD can be productively reframed as a process of stress-response exhaustion. In this view, degeneration begins when the adaptive systems that maintain disc cell viability and matrix homeostasis under chronic microenvironmental stress lose amplitude, flexibility or recovery capacity. Hypoxia-inducible factor signalling, AMPK-mTOR metabolic sensing, autophagy and mitophagy, unfolded-protein and integrated stress responses, and redox buffering are initially protective. With ageing, endplate dysfunction, nutrient diffusion failure, acidosis, abnormal mechanical loading and organelle damage, these same systems can become insufficient or maladaptive, creating a degenerative tipping point. Downstream consequences include senescence, sterile inflammation, cell death, matrix collapse and neuroimmune conversion to painful disease. This framework does not replace established mechanisms of IVDD; rather, it orders them along a temporal axis from adaptation to exhaustion. It also suggests stage-specific therapeutic logic: preserve adaptive reserve early, prevent stress-response collapse, suppress senescence and sterile inflammation, and target neuroimmune sensitization in painful degeneration.<\/jats:p>","DOI":"10.3389\/fcell.2026.1898234","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:34:47Z","timestamp":1782970487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Stress-response exhaustion in intervertebral disc degeneration"],"prefix":"10.3389","volume":"14","author":[{"given":"Jinghui","family":"Song","sequence":"first","affiliation":[{"name":"Orthopedics, Jingzhou Hospital Affiliated to Yangtze University","place":["Jingzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[{"name":"Orthopedics, Jingzhou Hospital Affiliated to Yangtze University","place":["Jingzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Ma","sequence":"additional","affiliation":[{"name":"Orthopedics, Jingzhou Hospital Affiliated to Yangtze University","place":["Jingzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1111\/j.1469-7580.2012.01551.x","article-title":"Intervertebral disc degeneration: evidence for two distinct phenotypes","volume":"221","author":"Adams","year":"2012","journal-title":"J. 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