ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2024; 20(5):1855-1870. doi:10.7150/ijbs.92371 This issue Cite
Research Paper
A novel A2a adenosine receptor inhibitor effectively mitigates hepatic fibrosis in a metabolic dysfunction-associated steatohepatitis mouse model
1. College of Pharmacy, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
2. Muscle Physiome Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
3. Department of Internal Medicine, Korea University College of Medicine, Seoul, 08308, Republic of Korea.
#Authors contributed equally to this work.
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.
Keywords: A2aAR, hepatic fibrosis, MASH, ZM241385, novel A2aAR antagonist RAD11 [4-(6-(methylamino)-2-(phenylethynyl)-9H-purin-9-yl)phenol]
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