{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:13:00Z","timestamp":1792084380943,"version":"4.4.0"},"reference-count":40,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Antioxidant compounds have repeatedly failed to modify the course of neurodegenerative and psychiatric disease, and the field concluded that oxidative stress is a consequence rather than a driver of neurodegeneration. This paper advances the hypothesis that the error was translational rather than conceptual, and that oxidative damage, redox state, regulatory reserve, disease activity, and accumulated injury are distinct biological dimensions that have been treated as interchangeable in trial design. Oxidative stress was defined from the outset as a disturbance of a regulated balance, and later as a disruption of control across thiol\/disulfide couples\u2014paired reduced and oxidized species whose ratios set the local redox state\u2014that are not mutually equilibrated. It was nonetheless investigated as accumulated damage and treated by subtraction: fixed doses of non-selective compounds, given to patients enrolled on clinical diagnosis, without prospective characterization of redox state or regulatory capacity. Four failure modes follow: wrong stage, wrong compound, wrong readout, wrong population. We engage the strongest counterevidence directly, including two trials that corrected compound selectivity and molecular stratification and still returned null results, define redox reserve operationally, propose a four-domain characterization framework for which no cut-points are yet established, and specify the conditions under which the hypothesis should be abandoned.<\/jats:p>","DOI":"10.3390\/ijms27188374","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From Damage to Dysregulation: Reframing Oxidative Stress and Redox Homeostasis in Central Nervous System Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5347-8067","authenticated-orcid":false,"given":"Leonard A.","family":"Lado","sequence":"first","affiliation":[{"name":"Lado Healing Institute, 9410 Fountain Medical Ct, Suite 200, Bonita Springs, FL 34135, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1126\/science.119.3097.623","article-title":"Oxygen poisoning and x-irradiation: A mechanism in common","volume":"119","author":"Gerschman","year":"1954","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/geronj\/11.3.298","article-title":"Aging: A theory based on free radical and radiation chemistry","volume":"11","author":"Harman","year":"1956","journal-title":"J. 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