A novel A2a adenosine receptor inhibitor effectively mitigates hepatic fibrosis in a metabolic dysfunction-associated steatohepatitis mouse model

Seojeong Park, Seohui Hwang, Jingyang Sun, Kyung Hwa Jeon, Naeun Sheen, Sumin Shin, Tae Hyun Kim, Young Sun Lee, Wonhyo Seo, Jae Sang Ryu, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Hepatic fibrosis exacerbates mortality and complications in progressive metabolic dysfunction-associated steatohepatitis (MASH). The role of the adenosine 2A receptor (A2aAR) in hepatic fibrosis within the context of MASH remains uncertain. This study aims to elucidate the involvement of the A2aAR signaling pathway and the efficacy of a novel potent A2aAR antagonist in treating hepatic fibrosis in MASH-induced mice fed a chlorine-deficient, L-amino acid-defined, high fat diet (CDAHFD). A2aAR overexpression in LX-2 cells increased fibrosis markers, whereas the known A2aAR antagonist, ZM241385, decreased these markers. A novel A2aAR antagonist, RAD11, not only attenuated fibrosis progression but also exhibited greater inhibition of the A2aAR signaling pathway compared to ZM241385 in mice with MASH, activated primary hepatocytes, and LX-2 cells. RAD11 exhibited a dual antifibrotic mechanism by targeting both activated HSCs and hepatocytes. Its superior antifibrotic efficacy over ZM241385 in the MASH condition stems from its ability to suppress A2aAR-mediated signaling, inhibit HSC activation, reduce hepatic lipogenesis in hepatocytes, and mitigate lipid accumulation-induced oxidative stress-mediated liver damage. This study has shed light on the relationship between A2aAR signaling and hepatic fibrosis, presenting RAD11 as a potent therapeutic agent for managing MASH and hepatic fibrosis.

Original languageEnglish
Pages (from-to)1855-1870
Number of pages16
JournalInternational Journal of Biological Sciences
Volume20
Issue number5
DOIs
StatePublished - 2024

Bibliographical note

Publisher Copyright:
© The author(s).

Keywords

  • A2aAR
  • hepatic fibrosis
  • MASH
  • novel A2aAR antagonist RAD11 [4-(6-(methylamino)-2-(phenylethynyl)-9H-purin-9-yl)phenol]
  • ZM241385

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