Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA.
Cell Res. 2023 Jul;33(7):516-532. doi: 10.1038/s41422-023-00820-4. Epub 2023 May 11.
Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability. Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.
细胞衰老（Cellular senescence）是一种应激诱导的、稳定的细胞周期停滞表型，可产生促炎微环境，导致慢性炎症和与年龄相关的疾病。确定驱动衰老而不是细胞凋亡的基本分子途径，可以识别出能够恢复组织内稳态的衰老细胞选择性溶解剂（senolytic agents）。在这里，我们发现血栓调节蛋白（thrombomodulin，THBD）信号是衰老细胞命运的关键分子决定因素。尽管 THBD 通常局限于内皮细胞，但在衰老哺乳动物组织和衰老细胞模型中，THBD 可迅速上调并在衰老程序的所有阶段中持续表达。从机制上讲，THBD 通过稳定早期内涵体中的多蛋白复合物来激活蛋白水解的正反馈信号通路，从而为衰老程序的不可逆性和确保衰老细胞的存活提供了分子基础。在治疗上，使用已获 FDA 批准的 vorapaxar 抑制或耗尽 THBD 信号，可有效消除衰老细胞并恢复肝纤维化模型中的组织内稳态。总的来说，这些结果揭示了蛋白水解 THBD 信号是衰老细胞存活所必需的保守生存途径，为与衰老相关的疾病提供了一种可用于药物开发的衰老细胞选择性溶解剂靶点。
