{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:38:00Z","timestamp":1786721880565,"version":"build-2736575974"},"reference-count":181,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ferroptosis-targeted therapies in Alzheimer\u2019s disease (AD) have yielded consistent preclinical evidence; however, their translation into clinical outcomes has remained elusive. This mismatch reflects a fundamental flaw that conceptualizes this peroxidative pathway as a single, stage-invariant druggable entity. Existing frameworks conflate acyl-CoA synthetase long-chain family member 4 (ACSL4) activity, a slow, constitutive, amyloid-responsive process, with oxidative execution, an acute 5-lipoxygenase (5-LOX) process driven by neuroinflammatory triggers operating on incompatible time scales. This conflation makes it structurally impossible to match as a therapeutic strategy to any individual patient. This review proposes the Substrate-Engine Model to resolve this translational paradox: ACSL4 constitutes the substrate arm, establishing membrane vulnerability detectable years before cognitive symptom onset, while 5-LOX constitutes the engine arm, catalyzing peroxidative neuronal death under neuroinflammatory conditions in prodromal-to-dementia stages. These arms are mechanistically noninterchangeable. Systematic network analysis confirms that ACSL4 and 5-LOX occupy nonredundant positions in the ferroptosis-AD interactome and reside in distinct Louvain communities with divergent cellular and disease-stage expression profiles that preclude compensatory pathway rerouting and provide a rationale for dual-arm targeting. Mechanistic reanalysis of \u201cREFLECT\u201d and \u201cTOMMORROW\u201d trials identified factors responsible for substrate-arm therapeutic failure. These analyses yield a four-subtype precision stratification framework (Types A\u2013D), anchored on two orthogonal biomarker axes. This framework repositions ferroptosis as a stage-specific therapeutic target, guiding the choice between prophylactic substrate depletion and acute engine suppression based on the patient\u2019s biomarker profile.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00163","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T20:02:03Z","timestamp":1785873723000},"page":"2044-2075","source":"Crossref","is-referenced-by-count":0,"title":["The Substrate-Engine\nModel of Ferroptosis: Stage-Specific\nTargeting of Acyl-CoA Synthetase Long-Chain Family Member 4 and 5-Lipoxygenase\nin Alzheimer\u2019s Disease"],"prefix":"10.1021","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0728-1629","authenticated-orcid":true,"given":"Anay","family":"Mondal","sequence":"first","affiliation":[{"name":"Chandigarh University , , , ,","place":["Mohali, Punjab, India, 140413"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3488-1092","authenticated-orcid":true,"given":"Reetuparna","family":"Acharya","sequence":"additional","affiliation":[{"name":"Chandigarh University , , , ,","place":["Mohali, Punjab, India, 140413"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3374-5792","authenticated-orcid":true,"given":"Smita","family":"Jain","sequence":"additional","affiliation":[{"name":"SVKM\u2019s NMIMS Deemed-to-be University , , ,","place":["Shirpur, India, 425405"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"2","key":"2026081411073988700_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the Global Prevalence of Dementia in 2019 and Forecasted\nPrevalence in 2050: An Analysis for the Global Burden of Disease Study\n2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"issue":"7","key":"2026081411073988700_cit2","doi-asserted-by":"publisher","first-page":"2898","DOI":"10.1002\/alz.12928","article-title":"Prevalence of Dementia\nin India: National and State Estimates from a Nationwide Study","volume":"19","author":"Lee","year":"2023","journal-title":"Alzheimer\u2019s Dementia"},{"issue":"1","key":"2026081411073988700_cit3","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early\nAlzheimer\u2019s Disease","volume":"388","author":"van Dyck","year":"2023","journal-title":"N. 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