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Hesperidin methyl chalcone (HMC), a water-soluble derivative of the flavonoid \u201chesperidin\u201d, exhibits antioxidant and anti-inflammatory effects. However, its effects on psoriasis have never been investigated. Therefore, this study aims to evaluate the ameliorative effects of HMC, alone and in combination with methotrexate (MTX) in an imiquimod (IMQ)-induced psoriasis mice model. Twenty-five adult female BALB\/c mice were randomized into five groups. Except for the control group, all mice received topical IMQ cream (62.5\u00a0mg of 5%) for six consecutive days; controls received Vaseline instead as a vehicle. Treated groups were orally administered MTX (1\u00a0mg\/kg body weight \u201cb.wt\u201d), HMC (500\u00a0mg\/kg b.wt), or their combination once daily. Our data revealed that HMC alone markedly attenuated skin erythema, scaling, epidermal hyperplasia, body weight loss, and histopathological alterations, while significantly (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001) suppressed splenomegaly and oxidative stress, and reduced the elevated levels of interleukin (IL)-23, IL-17A, and cyclooxygenase-2, as well as downregulated the expression of tumor necrosis factor-\u03b1. Importantly, the combination of HMC with MTX demonstrated a significant superior efficacy compared to either agent alone, suggesting potential additive or synergistic benefits. In conclusion, this study provides the first preclinical evidence that HMC, particularly in combination with MTX, ameliorates IMQ-induced psoriasis via modulation of inflammatory cytokines, oxidative stress, and histopathological damage. These findings suggest its potential as a therapeutic candidate that warrants further preclinical and clinical investigation in plaque-type psoriasis.\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04811-7","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T19:58:49Z","timestamp":1765569529000},"page":"7477-7494","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hesperidin methyl chalcone alleviates imiquimod-induced psoriasis in mice: effects alone and in combination with methotrexate"],"prefix":"10.1007","volume":"399","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2646-936X","authenticated-orcid":false,"given":"Hagar W.","family":"Abdelrahman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3676-952X","authenticated-orcid":false,"given":"Shadia M.","family":"Kadry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5377-0215","authenticated-orcid":false,"given":"Wafaa A.","family":"Morsy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2350-4208","authenticated-orcid":false,"given":"Marwa T.","family":"Hassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"4811_CR1","doi-asserted-by":"crossref","unstructured":"Abbas AH, Abbood MS, Ridha-Salman H, Fakhri SA, Abbas ZH, Al-Athari AJH (2025) Suppressive effect of topical moxifloxacin on imiquimod-induced model of psoriasis in mice. 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