靶向非典型G蛋白偶联受体信号通路治疗心脏纤维化
Targeting an atypical G protein-coupled receptor signaling pathway for cardiac fibrosis therapy
心脏纤维化独立预测心力衰竭不良结局，但目前没有美国食品药品监督管理局批准的直接靶向心脏纤维化重构的疗法。研究者建立以人诱导多能干细胞为核心的药物发现流程，通过高通量筛选找到先导抗纤维化化合物CGS15943，并在人心肌成纤维细胞、三维工程心脏组织和心力衰竭动物模型中验证。机制上，腺苷受体亚型汇聚于G蛋白βγ亚基，激活磷脂酰肌酶3-激酶-AKT和YAP通路，CGS可抑制该轴，减少纤维化基因表达和成纤维细胞活化，提示这一通路是潜在治疗靶点。
为什么推荐给您：首次提出腺苷受体-Gβγ信号作为心脏纤维化靶点，多平台验证，但尚处临床前。
不需要生物学背景，多打比方
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摘要Abstract
Cardiac fibrosis independently predicts adverse outcomes in heart failure (HF), yet no Food and Drug Administration-approved therapy directly targets fibrotic remodeling in the heart. To address this unmet clinical need, we used a multidimensional drug discovery pipeline centered on a human induced pluripotent stem cell (iPSC)-based platform. Through high-throughput screening, we identified CGS15943 (CGS) as the lead antifibrotic compound and validated its activity in human cardiac fibroblasts, three-dimensional engineered heart tissues, and animal models of HF. Mechanistic studies revealed an atypical adenosine receptor (AR)-dependent signaling pathway in which AR subtypes converge on Gβγ (the βγ subunits of heterotrimeric GTP-binding proteins) to activate phosphoinositide 3-kinase (PI3K)-AKT and yes-associated protein (YAP). CGS suppressed this signaling axis, thereby reducing fibrotic gene expression and fibroblast activation. These findings establish AR-driven Gβγ signaling as a potential therapeutic target for cardiac fibrosis.