Simultaneous Multi-Receptor Adenosine Antagonism Reduces Scar Formation in Human Heart Models

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Summary of  Science  https://doi.org/10.1126/science.aej5896 
Dr. Hao Zhang  et al.

Points

Researchers at the Stanford Cardiovascular Institute identified a shared non canonical signaling pathway through which three distinct adenosine receptors activate cardiac fibroblasts and promote scar tissue formation.
High throughput screening of approximately four thousand bioactive compounds in human stem cell models identified the pan adenosine antagonist CGS15943 as a lead anti fibrotic candidate.
Mechanistic experiments revealed that adenosine receptor subtypes A1 A2A and A2B converge on G beta gamma subunit signaling rather than their divergent canonical pathways.
Simultaneous multi receptor blockade or direct inhibition of G beta gamma reduced tissue stiffness and preserved contraction in three dimensional engineered human heart tissues and mouse models.
Authors concluded that targeting this shared convergence point provides a druggable mechanism to attenuate cardiac fibrosis and potentially treat scar tissue formation in other organs.

Summary

This study evaluated a novel therapeutic pathway targeting cardiac fibrosis, the progressive deposition of scar tissue that impairs myocardial compliance and accelerates heart failure. Published in Science by researchers at the Stanford Cardiovascular Institute in collaboration with UCLA, Boston University, MD Anderson Cancer Center, the University of Arizona, and Greenstone Biosciences, the investigation focused on non-canonical G protein-coupled receptor (GPCR) signaling. The research sought to identify common molecular convergence points driving cardiac fibroblast activation across multiple adenosine receptor (AR) subtypes.

To screen potential therapeutic agents, researchers utilized human induced pluripotent stem cell (iPSC)-derived cardiac models and tested approximately 4,000 bioactive compounds for their ability to attenuate fibroblast activation without inducing cardiotoxicity in cardiomyocytes or vascular cells. The pan-adenosine receptor antagonist CGS15943 (CGS) was identified as the lead candidate. Mechanistic analyses revealed that three distinct adenosine receptors—subtypes A1, A2A, and A2B—converge on non-canonical Gβγ subunit signaling rather than their traditional, divergent Gα pathways. Concurrent inhibition of all three receptors or targeted blockade of downstream Gβγ signaling produced robust anti-fibrotic effects in primary human cardiac fibroblasts, patient-derived cardiomyopathy cells, and three-dimensional engineered human heart tissues.

In mouse models of established cardiac fibrosis, CGS administration and selective Gβγ blockade significantly attenuated further collagen deposition, reduced tissue stiffness, and prevented functional decline. Parallel anti-fibrotic responses observed in human keloid fibroblasts and mouse dermal fibrosis models indicate broader systemic applicability. The authors conclude that targeting the shared AR-Gβγ signaling axis offers a promising strategy to overcome the limitations of single-receptor subtype antagonism in treating cardiac fibrosis and potentially fibrotic disorders in other organs.

Link to the article: https://www.science.org/doi/10.1126/science.aej5896?referrer=https%3A%2F%2Fmedicalxpress.com%2F

References

Zhang, H., Shivnaraine, R. V., Ren, L., Thai, P. N., Janicot, R., Zhu, W., Huang, R., Siepe, D. H., Tu, C., Liu, W., Maziarz, M., Deutsch, J. C., Liu, Y., Liu, C., Shin, D. H., Kim, H., Chandy, M., Kalocsay, M., Chiamvimonvat, N., … Wu, J. C. (2026). Targeting an atypical G protein–coupled receptor signaling pathway for cardiac fibrosis therapy. Science, 393(6818), eaej5896. https://doi.org/10.1126/science.aej5896