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Its pathophysiology extends beyond energy imbalance to encompass chronic redox disruption. Expansion of adipose tissue, particularly in visceral depots, exceeds mitochondrial capacity, impairs antioxidant defenses such as superoxide dismutase, catalase, and glutathione peroxidase, and perpetuates chronic low-grade inflammation via nuclear factor kappa B (NF-kB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathways. This review synthesizes preclinical evidence for diverse interventions, including vitamins A, B, C, E, and D; minerals such as zinc and selenium; amino acids such as N-acetylcysteine (NAC), L-carnitine, and taurine; various antioxidant compounds; and approved drugs including metformin, exenatide, fenofibrate, and orlistat. Despite differing structures and mechanisms, these interventions converge on restoring redox balance by activating nuclear factor erythroid 2\u2013related factor 2 (Nrf2)\/AMP-activated protein kinase (AMPK), increasing glutathione, and stabilizing mitochondria. However, translation of these preclinical findings into clinical practice requires further clarification of dosing, delivery methods, and long-term safety.<\/jats:p>","DOI":"10.3390\/ph19091414","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:53:28Z","timestamp":1788789208000},"page":"1414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oxidative Stress as a Pathophysiological Core of Obesity: Preclinical Evidence for Antioxidant-Based Therapy Strategies"],"prefix":"10.3390","volume":"19","author":[{"given":"Mariana Maciel","family":"Pereira","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Farmacologia e Qu\u00edmica Medicinal, Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolinne Souza de","family":"Amorim","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline Cristina Casimiro de Albuquerque","family":"Gomes","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helber da Maia","family":"Valenca","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Morfol\u00f3gicas, Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9860-5272","authenticated-orcid":false,"given":"Mariana","family":"Renovato-Martins","sequence":"additional","affiliation":[{"name":"Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niter\u00f3i 24210-201, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-608X","authenticated-orcid":false,"given":"Manuella","family":"Lanzetti","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1868-9905","authenticated-orcid":false,"given":"Samuel Santos","family":"Valenca","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8563-6432","authenticated-orcid":false,"given":"Jo\u00e3o Alfredo de","family":"Moraes","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S2213-8587(24)00316-4","article-title":"Definition and diagnostic criteria of clinical obesity","volume":"13","author":"Rubino","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.2147\/DMSO.S540103","article-title":"Obesity and its comorbidities: Current treatment options, emerging biological mechanisms, future perspectives and challenges","volume":"18","author":"Wang","year":"2025","journal-title":"Diabetes Metab. 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