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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Cynaroside Attenuates Ethinylestradiol-Induced Cholestatic Liver Injury by Modulating the FXR/BSEP/CYP7A1/SHP Axis

  • Amany M. Hamed1
  • Doha M. Al-Nouri2
  • Nadia S. Mahrous3
  • Asmaa Sabry Bassit4
  • Azza M. A. Abouelella5
  • Asmaa Hassan6
  • Gehad S. Mokhtar7
  • Ghada M. Ahmad8
  • Ahmed S. Osman9
  • Ahmed R. H. Ahmed10
  • Aya A. E. Mahgoob11
  • Shymaa A. Thabet12
5 more authors
  • Hany M. R. Abdel-Latif13
  • Ghalia Shamlan2
  • Haifeng Zhao14
  • Ammar Al-Farga15
  • Safaa S. Soliman16
16 affiliations
  1. 1Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt
  2. 2Department of Food and Nutrition Sciences, College of Food and Agriculture Sciences, King Saud University, Riyadh 11495, Saudi Arabia
  3. 3Department of Zoology, Faculty of Science, South Valley University, Qena 83523, Egypt
  4. 4Anatomy & Embryology Department, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
  5. 5Department of Clinical Pharmacology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
  6. 6Department of Physiology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
  7. 7Department of Molecular Biology, Faculty of Applied Biotechnology, Merit University, Sohag 82755, Egypt
  8. 8Department 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
  9. 9Department of Biochemistry, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt
  10. 10Department of Pathology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
  11. 11Technology of Medical Laboratory Department, Higher Technology Institute of Applied Health Sciences, Badr Academy for Technology and Sciences, Badr City 11829, Egypt
  12. 12Central Research Center, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
  13. 13Department of Poultry and Fish Diseases, Faculty of Veterinary Medicine, Alexandria University, Alexandria 26571, Egypt
  14. 14School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
  15. 15Department of Biological Sciences, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
  16. 16Department of Zoology, Faculty of Science, Minia University, Minia 61519, Egypt
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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.

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Cite

BibTeXRIS
BibTeX
@article{hamed2026cynaroside,
  title = {{Cynaroside Attenuates Ethinylestradiol-Induced Cholestatic Liver Injury by Modulating the FXR/BSEP/CYP7A1/SHP Axis}},
  author = {Amany M. Hamed and Doha M. Al-Nouri and Nadia S. Mahrous and Asmaa Sabry Bassit and Azza M. A. Abouelella and Asmaa Hassan and Gehad S. Mokhtar and Ghada M. Ahmad and Ahmed S. Osman and Ahmed R. H. Ahmed and Aya A. E. Mahgoob and Shymaa A. Thabet and Hany M. R. Abdel-Latif and Ghalia Shamlan and Haifeng Zhao and Ammar Al-Farga and Safaa S. Soliman},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27198839},
  url = {https://www.mdpi.com/1422-0067/27/19/8839},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cynaroside Attenuates Ethinylestradiol-Induced Cholestatic Liver Injury by Modulating the FXR/BSEP/CYP7A1/SHP Axis
AU  - Amany M. Hamed
AU  - Doha M. Al-Nouri
AU  - Nadia S. Mahrous
AU  - Asmaa Sabry Bassit
AU  - Azza M. A. Abouelella
AU  - Asmaa Hassan
AU  - Gehad S. Mokhtar
AU  - Ghada M. Ahmad
AU  - Ahmed S. Osman
AU  - Ahmed R. H. Ahmed
AU  - Aya A. E. Mahgoob
AU  - Shymaa A. Thabet
AU  - Hany M. R. Abdel-Latif
AU  - Ghalia Shamlan
AU  - Haifeng Zhao
AU  - Ammar Al-Farga
AU  - Safaa S. Soliman
PY  - 2026
DA  - 2026/10/03
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27198839
UR  - https://www.mdpi.com/1422-0067/27/19/8839
AB  - 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.
SN  - 1422-0067
ER  -