September 28, 2026Science
Targeting an atypical G protein–coupled receptor signaling pathway for cardiac fibrosis therapy
Key result
CGS15943 reduces fibroblast activation in preclinical HF models via atypical adenosine receptor suppression.
Why the study?
Cardiac fibrosis predicts adverse outcomes in heart failure, yet no FDA-approved therapy directly targets fibrotic remodeling in the heart.
Does CGS15943 reduce fibrotic gene expression and fibroblast activation in preclinical models of cardiac fibrosis?
Population
Human iPSC-based platform, human cardiac fibroblasts, 3D engineered heart tissues, and animal models of heart failure
Comparison
CGS15943 (CGS) vs no treatment or control
Design
Preclinical multidimensional drug discovery pipeline
Authors
Discussion
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Member takes
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“These adenosine receptors normally signal through different G-alpha proteins, but here we show that all three were signaling in an unconventional way. That common, unconventional G-beta-gamma signal helps explain why blocking the receptors together had a much stronger antifibrotic effect than targeting them one at a time.”
“This study identifies a common signal through which several adenosine receptors can drive cardiac fibroblast activation. 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.”
“We wanted a screening platform that would allow for rapid exclusion of any drugs that harmed the heart, not just one that identifies compounds that stopped scarring.”
Overview
CGS15943 shows antifibrotic activity in animal HF models; leaves open whether atypical adenosine receptor inhibition merits human trials.
Key Points
- Identify small-molecule therapeutics and targetable molecular mechanisms to directly reverse or prevent cardiac fibrosis in heart failure.
- Screened candidate antifibrotic compounds using a human induced pluripotent stem cell (iPSC)-based drug discovery platform.
- Tested the lead compound CGS15943 across human cardiac fibroblasts, 3D engineered heart tissues, and animal heart failure models.
- Profiled downstream signaling pathways involving adenosine receptor subtypes, Gβγ subunits, PI3K-AKT, and YAP.
- Identified CGS15943 as an effective antifibrotic agent that suppresses fibrotic gene expression and cardiac fibroblast activation across all preclinical models.
- Delineated an atypical signaling cascade where adenosine receptors converge on Gβγ subunits to activate PI3K-AKT and YAP, which is inhibited by CGS15943.
Structured PICO
Does CGS15943 reduce fibrotic gene expression and fibroblast activation in preclinical models of cardiac fibrosis?
P
Population
Human induced pluripotent stem cell (iPSC)-based platform, human cardiac fibroblasts, three-dimensional engineered heart tissues, and animal models of heart failure
I
Intervention
CGS15943 (CGS)
O
Outcome
Fibrotic gene expression and fibroblast activationsurrogate
CGS15943 was identified as a lead antifibrotic compound that reduces cardiac fibrosis by targeting an atypical adenosine receptor-driven Gβγ signaling pathway, establishing a potential new therapeutic target for heart failure.
Cite This Study
Zhang et al. (2026) studied Cardiac fibrosis in heart failure. CGS15943 (CGS) was evaluated on Fibrotic gene expression and fibroblast activation. CGS15943 suppressed an atypical adenosine receptor-dependent signaling pathway, reducing fibrotic gene expression and fibroblast activation in preclinical models of heart failure.