{ "abstract": "Cholestatic liver diseases are characterized by disrupted bile acid homeostasis, oxidative stress, and inflammation, ultimately leading to progressive hepatic injury. Although ursodeoxycholic acid (UDCA) remains the standard pharmacological therapy, its therapeutic efficacy is limited in several cholestatic conditions. This study investigated the hepatoprotective effects of cynaroside (CYN), a naturally occurring flavonoid glycoside, against ethinylestradiol (EE)-induced cholestatic liver injury and explored its underlying molecular mechanisms. Female Wistar rats were randomly allocated into four groups (n = 7): control, EE, EE + CYN, and EE + UDCA. Liver function indices, bile acids, cholesterol, oxidative stress and inflammatory biomarkers, histopathology, immunohistochemistry, Western blotting, qRT-PCR, and molecular docking analyses were performed. EE administration induced pronounced cholestatic liver injury, as evidenced by impaired liver function, hepatic accumulation of bile acids and cholesterol, oxidative imbalance, inflammatory responses, and marked histopathological alterations. CYN significantly ameliorated these biochemical and histological abnormalities, reduced hepatic bile acid and cholesterol accumulation, restored redox homeostasis, and attenuated inflammatory responses. Mechanistically, CYN modulated the hepatic FXR/BSEP/CYP7A1/SHP regulatory network, modulated hepatic FXR and Nrf2 protein expression, suppressed NF-κB activation, and favorably regulated TNF-α, IL-1β, and BCL2 expression. Histopathological and immunohistochemical findings further confirmed substantial preservation of hepatic architecture following CYN treatment. Molecular docking revealed favorable interaction of CYN with the FXR ligand-binding domain, with a predicted binding free energy of −8.18 kcal/mol, comparable to that of UDCA (−7.95 kcal/mol). Cynaroside attenuated EE-induced cholestatic liver injury by improving bile acid homeostasis and mitigating oxidative and inflammatory responses, potentially by modulating FXR-associated signaling and its downstream regulatory network. Collectively, the results provide a rationale for continued investigation of cynaroside in the context of cholestatic liver injury.", "abstract_shown": true, "affiliations": [ "Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt", "Department of Food and Nutrition Sciences, College of Food and Agriculture Sciences, King Saud University, Riyadh 11495, Saudi Arabia", "Department of Zoology, Faculty of Science, South Valley University, Qena 83523, Egypt", "Anatomy & Embryology Department, Faculty of Medicine, Sohag University, Sohag 82524, Egypt", "Department of Clinical Pharmacology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt", "Department of Physiology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt", "Department of Molecular Biology, Faculty of Applied Biotechnology, Merit University, Sohag 82755, Egypt", "Department of Medical Laboratory Technology, Faculty of Applied Health Sciences Technology, Pharos University in Alexandria, Canal El Mahmoudia Street, Beside Green Plaza Complex, Alexandria 21648, Egypt", "Department of Biochemistry, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt", "Department of Pathology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt", "Technology of Medical Laboratory Department, Higher Technology Institute of Applied Health Sciences, Badr Academy for Technology and Sciences, Badr City 11829, Egypt", "Central Research Center, Faculty of Medicine, Sohag University, Sohag 82524, Egypt", "Department of Poultry and Fish Diseases, Faculty of Veterinary Medicine, Alexandria University, Alexandria 26571, Egypt", "School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China", "Department of Biological Sciences, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia", "Department of Zoology, Faculty of Science, Minia University, Minia 61519, Egypt" ], "article_type": "research article", "arxiv": null, "author_total": 17, "authors": [ { "affs": [ 0 ], "name": "Amany M. Hamed", "orcid": "0000-0002-5995-8358" }, { "affs": [ 1 ], "name": "Doha M. Al-Nouri", "orcid": "0000-0002-1230-1471" }, { "affs": [ 2 ], "name": "Nadia S. Mahrous" }, { "affs": [ 3 ], "name": "Asmaa Sabry Bassit" }, { "affs": [ 4 ], "name": "Azza M. A. Abouelella" }, { "affs": [ 5 ], "name": "Asmaa Hassan" }, { "affs": [ 6 ], "name": "Gehad S. Mokhtar" }, { "affs": [ 7 ], "name": "Ghada M. Ahmad", "orcid": "0000-0002-6824-5683" }, { "affs": [ 8 ], "name": "Ahmed S. Osman" }, { "affs": [ 9 ], "name": "Ahmed R. H. Ahmed", "orcid": "0000-0003-2923-7012" }, { "affs": [ 10 ], "name": "Aya A. E. Mahgoob" }, { "affs": [ 11 ], "name": "Shymaa A. Thabet" }, { "affs": [ 12 ], "name": "Hany M. R. Abdel-Latif", "orcid": "0000-0001-8761-1493" }, { "affs": [ 1 ], "name": "Ghalia Shamlan", "orcid": "0000-0002-3095-3430" }, { "affs": [ 13 ], "name": "Haifeng Zhao", "orcid": "0000-0001-6009-3526" }, { "affs": [ 14 ], "name": "Ammar Al-Farga", "orcid": "0000-0002-0233-5539" }, { "affs": [ 15 ], "name": "Safaa S. Soliman" } ], "bibtex": "https://research.draconitic.com/paper/db6fft3hgnndz.bib", "cited_by": 0, "doi": "10.3390/ijms27198839", "fulltext_url": "https://europepmc.org/articles/PMC13665009", "id": "db6fft3hgnndz", "issns": [ "1422-0067" ], "landing_url": "https://www.mdpi.com/1422-0067/27/19/8839", "language": "eng", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "3004|Drug-Induced Hepatotoxicity and Protection" ] ], "openalex": "W7220414465", "pdf_url": "https://europepmc.org/articles/PMC13665009?pdf=render", "pmcid": "PMC13665009", "pmid": "42884083", "published": "2026-10-03", "publisher": "MDPI AG", "ris": "https://research.draconitic.com/paper/db6fft3hgnndz.ris", "sources": [ { "first_seen": "2026-10-30T12:18:55Z", "native_id": "10.3390/ijms27198839", "source": "crossref", "url": "https://www.mdpi.com/1422-0067/27/19/8839" }, { "first_seen": "2026-10-30T12:19:00Z", "native_id": "MED:42884083", "source": "europepmc", "url": "https://europepmc.org/article/MED/42884083" } ], "subjects": [ { "field": "medicine", "origin": "openalex:3004|Drug-Induced Hepatotoxicity and Protection", "subfield": "pharmacology-toxicology" } ], "title": "Cynaroside Attenuates Ethinylestradiol-Induced Cholestatic Liver Injury by Modulating the FXR/BSEP/CYP7A1/SHP Axis", "title_text": "Cynaroside Attenuates Ethinylestradiol-Induced Cholestatic Liver Injury by Modulating the FXR/BSEP/CYP7A1/SHP Axis", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:00Z", "url": "https://research.draconitic.com/paper/db6fft3hgnndz", "venue": "International Journal of Molecular Sciences", "versions": [] }