{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T03:03:52Z","timestamp":1779678232418,"version":"3.53.1"},"reference-count":66,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"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\/Objectives: Non-alcoholic steatohepatitis (NASH) represents a worldwide health challenge with limited currently available effective treatment. The present analysis was designed to examine possible therapeutic advances of Ambrisentan (AMB) targeting multiple features of hepatic damage in dexamethasone (DEXA)-provoked nonalcoholic steatohepatitis (NASH) in rats. Methods: Rats were randomly divided into four groups: a control group; a DEXA group; and two AMB-treated groups that received AMB (5 or 10 mg\/kg\/day orally for a week) before and concomitantly with DEXA (8 mg\/kg\/day, i.p.) for 6 days. After completion of the experiment, serum markers of liver function and lipid profile were assessed, and hepatic histopathological alterations were examined. Results: AMB (mainly at 10 mg\/kg\/day) markedly ameliorated liver-function parameters, the lipid profile, and hepatic histopathological characteristics in DEXA-treated rats. MDA was reduced, whereas GSH, GPX4 and Nrf2 were heightened, indicating elevated oxidative damage. Moreover, AMB efficiently reinstated iron homeostasis and aggravated iron overload by altering serum iron, hepatic ferritin, transferrin and hepcidin. AMB decreased serum calcium and hepatic calcineurin A levels, followed by a reduction in hepatic autophagy biomarker Beclin-1. AMB downregulated pro-inflammatory biomarkers NF-\u03baB, IL-6 and TGF-\u03b21. Moreover, it notably repressed the hepatic gene expression of ferritinophagy biomarker NCOA4, with elevated FTH1 hepatic gene expression. Moreover, AMB ameliorated DEXA-induced changes in endothelial and vascular function by increasing hepatic PGI2 and cGMP and lowering ET-1 and iNOS. Conclusions: AMB improved DEXA-induced NASH, primarily through its action on endothelin pathways, with associated reductions in inflammation and the downstream processes of ferroptosis, ferritinophagy, lipophagy, and autophagy.<\/jats:p>","DOI":"10.3390\/ph19050798","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T02:32:28Z","timestamp":1779676348000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ambrisentan Exhibits Hepatoprotective Effects Against NASH-Associated Hepatic Injury in Dexamethasone-Treated Rats Through Regulation of Inflammation, Ferroptosis and Autophagy"],"prefix":"10.3390","volume":"19","author":[{"given":"Naif S.","family":"Alharbi","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, ElGomhoria Street, Mansoura 35516, Egypt"},{"name":"Assistant Deputy Ministry for Human Resources Services, Ministry of Health, Madinah, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8590-2622","authenticated-orcid":false,"given":"Manar A.","family":"Nader","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, ElGomhoria Street, Mansoura 35516, Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Health Science Technology, Mansoura National University, Gamasa 7731168, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-5378","authenticated-orcid":false,"given":"Marwa S.","family":"Serrya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, ElGomhoria Street, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2283-5327","authenticated-orcid":false,"given":"Marwa E.","family":"Abdelmageed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, ElGomhoria Street, Mansoura 35516, Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Health Science Technology, Mansoura National University, Gamasa 7731168, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.eprac.2021.12.010","article-title":"Fatty Liver Through the Ages: Nonalcoholic Steatohepatitis","volume":"28","author":"Younossi","year":"2022","journal-title":"Endocr. 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