Greenstone Biosciences today announced a study published in the journal Science that identifies an unexpected signaling mechanism involved in cardiac fibrosis. Conducted by researchers from Stanford University, UCLA, Boston University, MD Anderson, and other academic institutions, the study found that several cell-surface receptors previously thought to signal through different pathways can converge on a common molecular signal that promotes the activation of scar-forming cells in the heart.
The researchers found that blocking these receptors together produced substantially greater antifibrotic effects than blocking any one receptor alone. The findings were supported across human cell and engineered heart tissue models and in mice, where targeting the pathway limited further cardiac scarring and functional decline.
Cardiac fibrosis is the accumulation of excess scar tissue in the heart. It stiffens the myocardium and impairs the heart’s ability to contract and relax. Despite its importance across cardiovascular disease, no approved therapy directly targets fibrotic remodeling in the heart.
The team screened approximately 4,000 bioactive compounds using cardiac fibroblasts derived from human induced pluripotent stem cells (iPSCs). Parallel testing in heart muscle and endothelial cells served as counterscreens for toxicity. CGS15943, a nonselective adenosine receptor antagonist, emerged as the leading antifibrotic compound without overt toxicity in these cardiovascular cell models.
“This study identifies a common signal through which several adenosine receptors can drive cardiac fibroblast activation,” said Joseph C. Wu, MD, PhD, director of the Stanford Cardiovascular Institute, co-founder of Greenstone Biosciences and a corresponding author of the study. “By combining human stem-cell models with mechanistic studies and animal experiments, we could connect a screening result to a specific biological pathway that warrants further therapeutic investigation.”
Three receptors converge on one fibrosis pathway
The researchers discovered that three adenosine receptors, known as A1, A2A and A2B, work together in an unexpected way. These receptors normally respond to adenosine, a signaling molecule that increases during cellular stress and tissue injury. Although the three receptors are traditionally understood to send different, and sometimes opposing, signals into cells, the study found that all three converge on a common signal called Gβγ that promotes fibroblast activation and fibrosis.
Blocking any one receptor produced only a limited effect. Blocking all three together substantially suppressed fibroblast activation. This shared pathway may help explain why previous attempts to target individual adenosine receptors in fibrosis have produced inconsistent results. Rather than searching for a single receptor responsible for the disease, the findings suggest that targeting points where multiple fibrosis-promoting signals come together may provide a more effective strategy. “These three receptors have long been studied separately, and through their Gα subunits they can signal in opposite directions,” said Hao Zhang, MD, assistant professor at UCLA and first author of the study, who initiated the research at Stanford. “We found that in cardiac fibroblasts they also share a common downstream signal, Gβγ — and that this shared arm is what drives fibrosis. That shifts the question from which receptor to block to where the signals converge.”
The researchers confirmed antifibrotic activity in primary human cardiac fibroblasts, activated fibroblasts from patients with cardiomyopathy, and three-dimensional engineered human heart tissues. In the engineered tissues, CGS15943 reduced stiffness and improved contraction and relaxation. In mice treated after cardiac fibrosis and dysfunction were established, it limited further disease progression but did not reverse existing collagen deposition.
“Screening in human cardiac fibroblasts allowed us to identify a potential therapeutic strategy for cardiac fibrosis, including the fibrosis that can develop as the heart adapts to chronic pressure overload in pulmonary arterial hypertension,” said Rabindra V. Shivnaraine, PhD, a co-first author of the study. “We then uncovered the underlying mechanism, showing why blocking several adenosine receptors together was more effective than targeting any one receptor alone.”
About the study
Zhang H, et al. “Targeting an atypical G protein-coupled receptor signaling pathway for cardiac fibrosis therapy.” Science 393, eaej5896 (2026). DOI: 10.1126/science.aej5896.
Greenstone Biosciences is a biotechnology company based in Stanford Research Park in Palo Alto, California. The company combines human iPSC-derived cells, organoids, and computational approaches to model disease, discover drugs, and assess safety. Its products and services support academic and industry research using new approach methodologies (NAMs) with human-relevant models.
