Forskolin alleviates cholestatic liver disease by inhibiting the Hippo/YAP-mediated ductular reaction and fibrosis progression

Theodor Bilharz Research Institute

Bibliographic Information

Authors: El-Maadawy W.H.; Hafiz E.; Mostafa A.; Hassany A.A.; Shafie N.S.; Lethy A.W.; El-Ahwany E.; Amer M.

Journal: European Journal of Pharmacology

Publisher: Elsevier B.V.

Publication Date: November 2025

Volume / Issue: Volume 1006

Article No.: 178182

ISSN: 142999

DOI: 10.1016/j.ejphar.2025.178182

Scopus: View on Scopus

PubMed: 40975472

Document Type: Article

Authors and Affiliations

El-Maadawy W.H., Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Hafiz E., Department of Electron Microscopy, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Mostafa A., Department of General Surgery, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Hassany A.A., Department of Bioinformatics and Genomics, College of Biotechnology, Misr University for Science and Technology (MUST), Giza, Egypt; Shafie N.S., Department of Bioinformatics and Genomics, College of Biotechnology, Misr University for Science and Technology (MUST), Giza, Egypt; Lethy A.W., Department of Bioinformatics and Genomics, College of Biotechnology, Misr University for Science and Technology (MUST), Giza, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Amer M., Department of Bioinformatics and Genomics, College of Biotechnology, Misr University for Science and Technology (MUST), Giza, Egypt

Abstract

Cholestatic liver disease (CLD) results from impaired bile flow, involving dysregulated Hippo/YAP signaling driving pathogenic ductular reaction (DR), inflammation, and fibrosis. Although ursodeoxycholic acid (UDCA) remains first-line therapy, most patients show inadequate response. Our computational screening identified forskolin (FSK), adenylate cyclases (ADCY1–10) activator, as a potential Hippo/YAP pathway modulator through cAMP elevation. Molecular docking confirmed FSK's stable binding across all human ADCY isoforms, supporting upstream cAMP's activation. Cholestatic injury was induced in rats via bile duct ligation (BDL). BDL-rats were treated with either FSK or UDCA. Relative to UDCA, FSK significantly improved liver function (ALT, AST, ALP, GGT) and cholestasis (bilirubin, bile acids) parameters. FSK markedly reduced inflammation markers (IL-6, IL-1β, CXCL1, and CXCL2) and attenuated fibrosis, as evidenced by restored Hydroxyproline levels, COL1A1, and α-SMA expressions. Histological analysis revealed that FSK preserved hepatic architecture, suppressed DR, and downregulated CK19/EpCAM expressions, whereas UDCA showed only partial improvement. Although UDCA significantly modulated Hippo/YAP signaling, FSK substantially activated the pathway through LATS1/2 and YAP1 phosphorylation, suppressing YAP/TEAD transcriptional activity, mediated through cAMP elevation. These findings indicate FSK's multi-target therapeutic actions, mitigating inflammation, DR, and fibrosis mediated by ADCY-cAMP-Hippo/YAP axis modulation. Given its superior efficacy over UDCA, FSK represents a promising therapeutic candidate for clinical translation in CLD. © 2025 Elsevier B.V.

Keywords

Bile duct ligation; Ductular reactions; Forskolin; Hepatic cholestasis; Hepatic fibrosis; Hippo/YAP pathway; Animals; Bile Ducts; Cholestasis; Colforsin; Cyclic AMP; Disease Progression; Hippo Signaling Pathway; Humans; Liver; Liver Cirrhosis; Liver Diseases; Male; Molecular Docking Simulation; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; YAP-Signaling Proteins; adenylate cyclase; alpha smooth muscle actin; bile acid; bilirubin; cytokine; gamma interferon; hydroxyproline; interleukin 1beta; interleukin 6; small interfering RNA; tumor necrosis factor; ursodeoxycholic acid; protein serine threonine kinase; YAP signaling protein; Yap1 protein, rat; adult; animal cell; animal experiment; animal model; animal tissue; apoptosis; Article; bile flow; cell proliferation; controlled study; down regulation; enzyme linked immunosorbent assay; extracellular matrix; fibrosis; flow cytometry; gene expression; immunofluorescence assay; immunohistochemistry; inflammation; liver cell; liver cell carcinoma; liver disease; liver fibrosis; liver function; molecular docking; nonhuman; protein expression; rat; real time polymerase chain reaction; RNA extraction; RNA sequencing; Sprague Dawley rat; Western blotting; animal; bile duct; disease exacerbation; drug effect; drug therapy; hippo signaling; human; metabolism; pathology

Citation Information

Scopus Citations: 3

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