{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:57:21Z","timestamp":1785430641465,"version":"3.56.0"},"reference-count":89,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, Timi\u0219oara, Romania"},{"id":[{"id":"https:\/\/ror.org\/00afdp487","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>(1) Background: Reactive oxygen species (ROS) act as physiological signaling mediators but contribute to oxidative damage, cellular dysfunction, and age-related disease when redox homeostasis fails. Forkhead box O4 (FOXO4) has emerged as a redox-sensitive regulator linking stress adaptation, antioxidant defense, and cellular senescence. This structured narrative review critically evaluates which redox- and aging-related conclusions are supported directly for FOXO4 and which remain inferred from other FOXO isoforms. (2) Methods: PubMed\/MEDLINE, Scopus, and Web of Science were searched from inception to May 2026; Google Scholar was used only for supplementary citation tracking and did not contribute a separate platform-level count. Of 420 records, 300 remained after deduplication, 110 full texts were assessed, and 89 publications were retained. FOXO4-related evidence was classified as directly FOXO4-specific (n = 18), FOXO-family\/conserved (n = 24), or extrapolated predominantly from FOXO1\/FOXO3\/DAF-16 (n = 20); 27 contextual publications on redox biology, senescence, disease, and NRF2 were tracked separately. (3) Results: The strongest FOXO4-specific evidence supports three mechanistic axes: cysteine-dependent redox sensing, stress-regulated nuclear trafficking and coactivator engagement through transportin-1 and p300\/CBP, and FOXO4\u2013p53-mediated survival of senescent cells. By contrast, direct FOXO4 regulation of commonly cited antioxidant targets, including SOD2, catalase, sestrins, and GADD45, remains insufficiently demonstrated and is inferred mainly from FOXO3 or broader FOXO-family studies. FOXO4-DRI has shown senolytic activity in preclinical models, including vascular endothelium, but has not been clinically validated. (4) Conclusions: FOXO4 is a redox-responsive transcriptional regulator with well-supported roles in cysteine-based signaling and senescent-cell survival, whereas its target-gene-level antioxidant program remains incompletely resolved. Clinical translation of FOXO4\u2013p53 disruption requires isoform- and tissue-specific validation, pharmacokinetic and delivery studies, long-term toxicology, and explicit assessment of p53-dependent tumor surveillance.<\/jats:p>","DOI":"10.3390\/antiox15070842","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T14:33:06Z","timestamp":1783089186000},"page":"842","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXO4 as a Redox-Sensitive Regulator of Antioxidant Defense and Cellular Senescence: Cysteine-Based Signaling, p53 Interaction, and Therapeutic Targeting"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4951-1702","authenticated-orcid":false,"given":"Diana-Maria","family":"Mateescu","sequence":"first","affiliation":[{"name":"Department of General Medicine, Doctoral School, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragos-Mihai","family":"Gavrilescu","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Dental District, Z\u0103gazului 3, One Floreasca Vista, Sector 1, 014261 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelina-Raluca","family":"Marinescu","sequence":"additional","affiliation":[{"name":"Discipline of Infectious Diseases, Department XIII, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8236-2205","authenticated-orcid":false,"given":"Ovidiu","family":"Rosca","sequence":"additional","affiliation":[{"name":"Discipline of Infectious Diseases, Department XIII, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Voichita Elena","family":"Lazureanu","sequence":"additional","affiliation":[{"name":"Discipline of Infectious Diseases, Department XIII, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian-Cosmin","family":"Ilie","sequence":"additional","affiliation":[{"name":"Department of Public Health and Sanitary Management, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"},{"name":"Centre for Translational Research and Systems Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3896-9599","authenticated-orcid":false,"given":"Camelia-Oana","family":"Muresan","sequence":"additional","affiliation":[{"name":"Legal Medicine, Timisoara Institute of Legal Medicine, 300041 Timisoara, Romania"},{"name":"Ethics and Human Identification Research Center, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"},{"name":"Discipline of Forensic Medicine, Bioethics, Deontology, and Medical Law, Department of Neuroscience, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Enache","sequence":"additional","affiliation":[{"name":"Legal Medicine, Timisoara Institute of Legal Medicine, 300041 Timisoara, Romania"},{"name":"Ethics and Human Identification Research Center, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"},{"name":"Discipline of Forensic Medicine, Bioethics, Deontology, and Medical Law, Department of Neuroscience, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive Oxygen Species (ROS) as Pleiotropic Physiological Signalling Agents","volume":"21","author":"Sies","year":"2020","journal-title":"Nat. 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