小分子直接下调β-连环蛋白可能为与靶向Wnt/β-连环蛋白途径的下游组分相比，提供了更有效的治疗抗癌干细胞的方法。然而，挑战在于很少有β-连环蛋白抑制剂被证明具有临床疗效，这在医学解决方案中存在着重大的差距。鉴于E-钙粘附素对β-连环蛋白具有天然亲和性，有理由认为设计用于增加E-钙粘附素表达的药物可能提供一种调节β-连环蛋白水平的替代方法。在本研究中，我们报告了从丹参素（DSS）中提取的丹参素C12和丹参素B8两种特定的酯类药物发现。非常显著的是，这些化合物表现出强效的能力降低β-连环蛋白的表达，并且同时改善了术后小鼠的总体生存率。此外，当这些药物与PD-L1检查点阻滞联合使用时，它们能够刺激增强的全身免疫反应，从而显著抑制原发性肿瘤的生长。深入的机制研究揭示了丹参素B8作为维生素D受体激动剂的作用，而不引起高钙血症。综上所述，我们的发现表明，由DSS衍生的小分子具有作为临床可行的β-连环蛋白失活治疗的潜力。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Small molecules directly downregulating β-catenin could potentially offer a more effective therapeutic approach for combating against cancer stem cells, as compared to targeting the downstream components of the Wnt/β-catenin pathway. The challenge, however, lies in the fact that very few β-catenin suppressors have proven clinically effective, leaving a significant gap in medical solutions. Given that E-cadherin has a natural affinity for β-catenin, it stands to reason that agents designed to increase E-cadherin expression might provide an alternative method of regulating β-catenin levels. In this study, we report our discovery of DSS-C12 and DSS-B8, specific ester-based drugs derived from Dan-Shen-Su (DSS) extracted from the herb Salvia miltiorrhiza. Remarkably, these compounds display a potent ability to downregulate β-catenin, while also improving overall survival in post-surgery mice. Additionally, when these drugs are used in combination with PD-L1 checkpoint blockade, they stimulate enhanced systemic immune responses leading to significant suppression of primary tumor growth. In-depth mechanistic studies revealed that DSS-B8 functions as a vitamin D receptor agonist without inducing hypercalcemic effects. Collectively, our findings indicate that DSS-derived small molecules have considerable potential as clinically viable therapeutic strategies for β-catenin deactivation.Copyright © 2023 Elsevier Inc. All rights reserved.