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

Title
A novel A2a adenosine receptor inhibitor effectively mitigates hepatic fibrosis in a metabolic dysfunction-associated steatohepatitis mouse model
Authors
ParkSeojeongHwangSunJingyangJeonKyung-HwaSheenNaeunShinSuminKimTae HyunLeeYoung-SunSeohuiSeoWonhyoRyuJae-SangKwonYoungjoo
Ewha Authors
권영주류재상전경화서원효박서정
SCOPUS Author ID
권영주scopus; 류재상scopus; 전경화scopus; 서원효scopus; 박서정scopus
Issue Date
2024
Journal Title
International Journal of Biological Sciences
ISSN
1449-2288JCR Link
Citation
International Journal of Biological Sciences vol. 20, no. 5, pp. 1855 - 1870
Keywords
A2aARhepatic fibrosisMASHnovel A2aAR antagonist RAD11 [4-(6-(methylamino)-2-(phenylethynyl)-9H-purin-9-yl)phenol]ZM241385
Publisher
Ivyspring International Publisher
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
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. © The author(s).
DOI
10.7150/ijbs.92371
Appears in Collections:
약학대학 > 약학과 > Journal papers
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