Ticagrelor attenuates cholestasis-induced liver fibrosis by inhibiting S1PR2-dependent Akt/ERK signaling, NLRP3 inflammasome activation

Theodor Bilharz Research Institute

Bibliographic Information

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

Journal: International Immunopharmacology

Publisher: Elsevier B.V.

Publication Date: January 2026

Volume / Issue: Volume 168

Article No.: 115834

ISSN: 15675769

DOI: 10.1016/j.intimp.2025.115834

Scopus: View on Scopus

PubMed: 41240716

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; Amer M., Department of Bioinformatics and Genomics, College of Biotechnology, Misr University for Science and Technology (MUST), Giza, 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; Hafiz E., Department of Electron Microscopy, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt

Abstract

S1PR2 activation is a pivotal player in chronic liver disease (CLD) progression through bile acid (BA) and sphingosine-1-phosphate (S1P) signaling. This signaling promotes ductular reaction (DR), NLRP3 inflammasome-driven inflammation, and fibrosis progression, making S1PR2 antagonism a promising therapeutic approach. Using structure-based virtual screening, Ticagrelor (TG) was identified as a potential S1PR2 inhibitor, demonstrating a strong predicted binding affinity (−10.1 kcal/mol) and stable interactions with key residues Thr 21, Arg 33, Asn 89, and His 271. Based on docking results, TG's hepatoprotective effects were evaluated in a bile duct ligation (BDL) rat model and compared to ursodeoxycholic acid (UDCA). TG showed greater efficacy in reducing liver injury and improving BA metabolism parameters compared to UDCA. Histological analysis revealed that TG preserved liver architecture and reduced DR, with decreased expression of biliary proliferation markers CK19 and EpCAM. Additionally, TG exhibited antifibrotic effects by downregulating COL1A1 and α-SMA expression. Mechanistically, TG inhibited S1PR2 pathway activation, lowered total BA levels, and suppressed the S1P/SphK2 axis. These effects involved reducing pAKT and pERK1/2 expression and inhibiting NLRP3 inflammasome activity, leading to diminished inflammatory responses. Our findings indicate that TG is a promising candidate for repurposing as a treatment for CLD, with benefits exceeding those of UDCA. Its ability to target S1PR2-mediated inflammation, fibrosis, and cholestasis suggests potential for broader applications in S1PR2-related inflammatory and fibrotic diseases. © 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Keywords

Akt/ERK1/2; Hepatic cholestasis; NLRP3 inflammasome pathway; S1PR2; Ticagrelor; Animals; Cholestasis; Humans; Inflammasomes; Liver; Liver Cirrhosis; Male; MAP Kinase Signaling System; Molecular Docking Simulation; NLR Family, Pyrin Domain-Containing 3 Protein; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Sphingosine-1-Phosphate Receptors; alpha smooth muscle actin; avapritinib; bile acid; ceftriaxone; collagen type I alpha 1 chain; cryopyrin; cytokeratin 19; elexacaftor; inflammasome; liver protective agent; lorlatinib; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; pralsetinib; protein kinase B; relugolix; talazoparib; telotristat ethyl; ursodeoxycholic acid; vericiguat; Nlrp3 protein, rat; sphingosine 1 phosphate receptor; sphingosine-1-phosphate receptor-2, rat; animal cell; animal experiment; animal model; animal tissue; antifibrotic activity; Article; bile acid metabolism; bile duct ligation; cell proliferation; controlled study; down regulation; histopathology; inflammation; liver fibrosis; liver protection; nonhuman; protein expression; rat; rat model; animal; complication; drug effect; drug therapy; etiology; human; MAPK signaling; metabolism; molecular docking; pathology; Sprague Dawley rat

Citation Information

Scopus Citations: 0

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