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The present study was designed to assess, for the first time, the potential therapeutic effect of rupatadine (RUP) in diethylnitrosamine (DEN)-induced liver fibrosis and to explore its possible mechanistic actions. For the induction of hepatic fibrosis, rats were treated with DEN (100\u00a0mg\/kg, i.p.) once weekly for 6 consecutive weeks, and on the 6th week, RUP (4\u00a0mg\/kg\/day, p.o.) was administered for 4\u00a0weeks. Treatment with RUP ameliorated changes in body weights, liver indices, liver function enzymes, and histopathological alterations induced by DEN. Besides, RUP amended oxidative stress, which led to the inhibition of PAF\/NF-\u03baB p65-induced inflammation, and, subsequently, prevention of TGF-\u03b21 elevation and HSCs activation as indicated by reduced \u03b1-SMA expression and collagen deposition. Moreover, RUP exerted significant anti-fibrotic and anti-angiogenic effects by suppressing Hh and HIF-1\u03b1\/VEGF signaling pathways. Our results highlight, for the first time, a promising anti-fibrotic potential of RUP in rat liver. The molecular mechanisms underlying this effect involve the attenuation of PAF\/NF-\u03baB p65\/TGF-\u03b21 and Hh pathways and, subsequently, the pathological angiogenesis (HIF-1\u03b1\/VEGF).<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s10787-023-01147-7","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T07:02:56Z","timestamp":1677049376000},"page":"845-858","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF\/NF-\u0138B p65\/TGF-\u03b21 and hedgehog\/HIF-1\u03b1\/VEGF trajectories"],"prefix":"10.1007","volume":"31","author":[{"given":"Manar A.","family":"Didamoony","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Atwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-2815","authenticated-orcid":false,"given":"Lamiaa A.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"1147_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/J.TAAP.2019.114697","author":"N Abdel-Rahman","year":"2019","unstructured":"Abdel-Rahman N, Sharawy MH, Megahed N, El-Awady MS (2019) Vitamin D3 abates BDL-induced cholestasis and fibrosis in rats via regulating Hedgehog pathway. 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