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The convergence of central neurotoxicity and peripheral immune dysregulation presents a unique therapeutic challenge requiring multi-target interventions. This study investigated the prophylactic efficacy of lycopene against dexamethasone-induced behavioral, neurochemical, oxidative, inflammatory, and immunological perturbations in rats. Thirty-two adult male Sprague-Dawley rats were randomly assigned to four groups (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098): normal control, dexamethasone (2\u00a0mg\/kg\/day\/intraperitoneal), lycopene (10\u00a0mg\/kg\/day\/orally), and dexamethasone+lycopene combination. Treatments were administered daily for 21 days. Behavioral assessments (forced swim test, tail suspension test) were conducted. In frontal cortex and hippocampal tissues, neurochemical markers (brain-derived neurotrophic factor, gamma-aminobutyric acid, and acetylcholinesterase activity), neurotransmitters (serotonin, dopamine), oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione, superoxide dismutase, catalase), inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), and caspase-3 were quantified. In serum, fasting blood glucose, insulin, liver and kidney function markers, oxidative stress markers, inflammatory cytokines (interleukin-4, tumor necrosis factor-alpha, interferon-gamma), cluster of differentiation 4 and 8 concentrations (CD4, CD8), and complete blood count were analyzed. Dexamethasone significantly (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) increased immobility time in behavioral tests, depleted serotonin and dopamine, elevated oxidative stress markers, and induced leukopenia with disrupted CD4\/CD8 ratios. Lycopene co-treatment reversed behavioral despair, restored neurotransmitter homeostasis, attenuated oxidative-inflammatory cascades, normalized immune cell populations, and improved metabolic parameters. Lycopene provides integrated multi-system protection against glucocorticoid-induced neurobehavioral and immunological dysfunction, positioning it as a potential promising nutritional adjunct for patients requiring chronic corticosteroid therapy.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-62143-9","type":"journal-article","created":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T16:24:53Z","timestamp":1784478293000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lycopene attenuates dexamethasone induced depression like behavior and immunological dysfunction via restoration of neuro-immune-metabolic homeostasis in rats"],"prefix":"10.1038","volume":"16","author":[{"given":"Hend A.","family":"Essa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"issue":"1","key":"62143_CR1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41572-020-0200-2","volume":"6","author":"SM Gold","year":"2020","unstructured":"Gold, S. 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