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

作者：Enrique Ángel‐Gomis, Esther Caparrós, Isabel Gómez‐Hurtado, Sebastián Martínez‐López, Ani Gasparyan, Anabel Fernández-Iglesias, Benedikt Simbrunner, Paula Boix, Jordi Gracia‐Sancho, Oriol Juanola, Rubén Francés · 发表于：Biomedicine & Pharmacotherapy · 年份：2025 · DOI：10.1016/j.biopha.2025.118804 · 被引用次数：1 · 研究领域：Liver physiology and pathology、Protein Kinase Regulation and GTPase Signaling、Liver Disease and Transplantation

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. Patients with cirrhosis and CCl 4 -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. Hepatic PAF-R increased in patients and the CCl 4 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 in...