{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T02:04:44Z","timestamp":1780538684147,"version":"3.54.1"},"reference-count":63,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Methotrexate-induced oxidative stress is mechanistically linked not only to hepatocellular injury but also to DNA damage, indicating that oxidative stress, hepatotoxicity, and genotoxicity represent interconnected manifestations of the same antifolate-driven toxic cascade. Methotrexate (MTX)-induced hepatotoxicity is characterized not only by oxidative stress, but also by progressive fibrotic remodeling driven by activation of the TGF-\u03b2\/SMAD signaling pathway. Objective: We aimed to examine the hepatoprotective effects of Loureirin B, with a particular focus on its anti-fibrotic potential and underlying molecular mechanisms in MTX-induced liver injury. Methods: Thirty female Wistar rats were assigned to normal control, MTX, and MTX + Loureirin B groups. Liver injury was induced with a single intraperitoneal MTX dose (20 mg\/kg), followed by oral administration of Loureirin B (50 mg\/kg\/day) for 10 days. Biochemical, molecular, and histopathological analyses were performed, including ALT, AST, ALP, MDA, SIRT1, TGF-\u03b2, SMAD3, hydroxyproline, and VEGF levels, alongside the evaluation of necrosis, fibrosis, and inflammatory infiltration. Results: MTX induced significant hepatic injury characterized by elevated serum ALT, AST, and ALP levels, increased oxidative stress, suppression of SIRT1, and increased TGF-\u03b2 and SMAD3 levels, accompanied by elevated collagen-associated markers. Loureirin B treatment significantly reduced the serum liver enzyme levels and oxidative stress, partially restored SIRT1 levels, and decreased fibrosis-associated markers, including hydroxyproline and VEGF. Although the TGF-\u03b2 levels were significantly reduced following Loureirin B treatment, the reduction in SMAD3 levels did not remain statistically significant after correction for multiple comparisons. Histopathological findings further demonstrated attenuation of fibrosis-associated changes and partial improvement in hepatic architecture. Conclusions: Loureirin B may exert protective effects against methotrexate-associated liver injury through the modulation of oxidative stress, partial restoration of SIRT1 levels, attenuation of profibrotic alterations associated with the TGF-\u03b2\/SMAD pathway, and modulation of VEGF-related responses.<\/jats:p>","DOI":"10.3390\/ph19060887","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"887","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loureirin B Attenuates Methotrexate-Induced Liver Injury Associated with Oxidative Stress, SIRT1 Alterations, and TGF-\u03b2\/SMAD3-Related Profibrotic Responses"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9297-4968","authenticated-orcid":false,"given":"\u0130rem","family":"Hengirmen Acu","sequence":"first","affiliation":[{"name":"Department of Dermatology and Venereology, Faculty of Medicine, Ufuk University, \u00c7ankaya, Ankara 06510, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oytun","family":"Erba\u015f","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, BAMER, Biruni University, Istanbul 34015, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.jaad.2008.02.039","article-title":"Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. 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