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This study established and characterized a rat model of acitretin-induced hepatotoxicity, aiming to explore potential biomarkers and mechanisms of protection. Fifty male Sprague\u2013Dawley rats were divided into five groups: control, acitretin, melatonin\u2009+\u2009acitretin, naringenin\u2009+\u2009acitretin, and combination treatment. Biochemical liver function tests, oxidative stress markers, inflammatory cytokines, histopathology, immunohistochemistry, and gene expression analyses were performed. Acitretin administration significantly elevated serum ALT, AST, ALP, LDH, and bilirubin levels, with concurrent reductions in serum albumin.Query Oxidative stress markers (MDA, nitrite) were increased, while antioxidant defenses (GSH, catalase) were compromised. Acitretin activated the HMGB1\/TLR4\/NF-\u03baB pathway, elevated TNF-\u03b1 and IL-6 levels, and triggered JAK\/STAT3 signaling, contributing to inflammation, apoptosis via caspase-3 activation, and early fibrotic changes marked by TGF-\u03b2 and MMP-9 upregulation. Treatment with melatonin and naringenin significantly mitigated these alterations, reducing oxidative stress, inflammation, apoptosis, and fibrogenesis. Notably, combination therapy provided superior hepatoprotection compared to individual treatments, suggesting a synergistic effect. These findings propose melatonin and naringenin as promising adjuncts to enhance the safety profile of acitretin therapy in clinical practice.<\/jats:p>","DOI":"10.1038\/s41598-025-16740-9","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:45:05Z","timestamp":1756316705000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Protective effects of melatonin and naringenin against acitretin induced hepatotoxicity via modulation of oxidative stress and inflammatory signaling"],"prefix":"10.1038","volume":"15","author":[{"given":"Samia S.","family":"Sokar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally E.","family":"Abu-Risha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2871-2603","authenticated-orcid":false,"given":"Mahmoud Abdelrahman","family":"Alkabbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila A.","family":"Ramadan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa E.","family":"Elsisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"16740_CR1","first-page":"73","volume":"6","author":"S David","year":"2010","unstructured":"David, S. & Hamilton, J. 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