2. Academic Validation
  3. Antagonizing epigenetically controlled PAF/PAF-R pathway improves liver function during experimental cirrhosis

Antagonizing epigenetically controlled PAF/PAF-R pathway improves liver function during experimental cirrhosis

  • Biomed Pharmacother. 2025 Dec:193:118804. doi: 10.1016/j.biopha.2025.118804.
Enrique Ángel-Gomis 1,  Esther Caparrós 2,  Isabel Gómez-Hurtado 3,  Sebastián Martínez-López 1,  Ani Gasparyan 1,  Anabel Fernández-Iglesias 4,  Benedikt Simbrunner 5,  Paula Boix 5,  Jordi Gracia-Sancho 4,  Oriol Juanola 6,  Rubén Francés 7
Affiliations

Affiliations

  • 1 Hepatic and Intestinal Immunobiology Group, Dpto. Medicina Clínica and Instituto IDIBE, Universidad Miguel Hernández, San Juan de Alicante, Spain; IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain.
  • 2 Hepatic and Intestinal Immunobiology Group, Dpto. Medicina Clínica and Instituto IDIBE, Universidad Miguel Hernández, San Juan de Alicante, Spain; IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
  • 3 IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
  • 4 CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain.
  • 5 Hepatic and Intestinal Immunobiology Group, Dpto. Medicina Clínica and Instituto IDIBE, Universidad Miguel Hernández, San Juan de Alicante, Spain.
  • 6 Hepatic and Intestinal Immunobiology Group, Dpto. Medicina Clínica and Instituto IDIBE, Universidad Miguel Hernández, San Juan de Alicante, Spain; IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: [email protected].
  • 7 Hepatic and Intestinal Immunobiology Group, Dpto. Medicina Clínica and Instituto IDIBE, Universidad Miguel Hernández, San Juan de Alicante, Spain; IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: [email protected].
PMID: 41270474 DOI: 10.1016/j.biopha.2025.118804
Abstract

Background and aims: Platelet-activating factor (PAF) phospholipid is mainly produced by macrophages and involved in pro-inflammatory responses. We evaluated the regulation of PAF-R gene expression during experimental cirrhosis and whether antagonizing its ligand PAF improves liver function and inflammation.

Methods: Patients with cirrhosis and CCl4-induced cirrhotic C57Bl/6 mice were included in the study. A subgroup of mice was treated with either PAF antagonist BN-52021 or a DNMT inhibitor, Aza, for two weeks before laparotomies. Sorted hepatic macrophages were subjected to a genome-wide DNA methylation study, and Ptafr expression analysed by Western Blot, qPCR, and immunohistochemistry in liver tissue. Immortalized Kupffer cells (imKCs) were stimulated with PAF and antigenic ligands. Cytokine and chemokine expression were measured. Biochemical and hepatic markers of liver damage were assessed.

Results: Hepatic PAF-R increased in patients and the CCl4 cirrhotic model. PAF antagonism reduced hepatic structural damage and improved endothelial function in cirrhotic mice. Also in vivo, PAF-R signalling pathway inhibition rebalanced hepatic cytokine response modifying the Th17-Treg axis in experimental cirrhosis. PAF-R was induced by CpG and TNF-α in vitro, and the PAF-R/PAF pathway stimulation elicited proinflammatory cytokine production in imKCs. PAF-R expression was controlled by Ptafr promoter CpGs demethylation in hepatic macrophages from cirrhotic mice. This mechanism was confirmed by targeting Enzymes inhibiting DNMTs in charge of DNA-methylation with Aza in imKCs.

Conclusion: PAF antagonist BN-52021 disrupts PAF-R/PAF signaling counteracting PAF-R overexpression, and ameliorates liver injury in cirrhotic mice. Ptafr expression is controlled by promoter DNA demethylation leading to PAFR overexpression in hepatic macrophages.

Keywords

Cirrhosis; DNA-methylation; Hepatic macrophages; Inflammation; Platelet-activating factor receptor.

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