Heart failure with preserved ejection fraction (HFpEF) presents a significant challenge to global healthcare systems due to its complex presentation. HFpEF presents with a normal or near-normal left ventricular ejection fraction, cardiac diastolic dysfunction, and a metabolic profile characterized by impaired inflammation and oxidative stress. There have been few valuable drug targets reported for HFpEF to date. Here, we discovered that schaftoside, an active component from licorice, has a significant protective effect on the cardiac remodeling induced by continuous infusion of angiotensin II (AngII), which leads to the HFpEF phenotype. Mechanistically, schaftoside has demonstrated the ability to ameliorate lysosomal dysfunction in both in vitro and in vivo models, thereby activating autophagy. Bioinformatic analyses based on proteome and phosphoproteome suggested that Ca2+/calmodulin-dependent protein kinase II (CaMKII) was a potential target for schaftoside. It was confirmed that schaftoside allosterically mediated CaMKII-δ conformation via targeting a unique active pocket near the ATP-binding site to inhibit protein phosphorylation and regulate the lysosomal autophagy pathway. Therefore, schaftoside represents the first small molecule identified to inhibit CaMKII-δ activity through allosteric inhibition, providing a novel candidate for alleviating cardiac metabolic imbalance in HFpEF.

中文翻译：

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Schaftoside 通过变构靶向 CaMKII-δ 调节自噬-溶酶体途径来改善 HFpEF


射血分数保留的心力衰竭 （HFpEF） 由于其复杂的表现而给全球医疗保健系统带来了重大挑战。HFpEF 表现为左心室射血分数正常或接近正常、心脏舒张功能障碍以及以炎症和氧化应激受损为特征的代谢特征。迄今为止，几乎没有报道的有价值的 HFpEF 药物靶点。在这里，我们发现夏夫托苷是甘草的一种活性成分，对持续输注血管紧张素 II （AngII） 诱导的心脏重塑具有显着的保护作用，从而导致 HFpEF 表型。从机制上讲，夏夫托苷已在体外和体内模型中证明能够改善溶酶体功能障碍，从而激活自噬。基于蛋白质组和磷酸化蛋白质组的生物信息学分析表明，Ca2+/钙调蛋白依赖性蛋白激酶 II （CaMKII） 是 chaftoside 的潜在靶点。经证实，黄糖苷通过靶向 ATP 结合位点附近的独特活性口袋来抑制蛋白质磷酸化并调节溶酶体自噬途径，从而变构介导 CaMKII-δ 构象。因此，夏夫托苷是第一个被鉴定出通过变构抑制抑制 CaMKII-δ 活性的小分子，为缓解 HFpEF 中的心脏代谢失衡提供了新的候选药物。