美国杜克大学王小凡研究组发现，拮抗不可逆的血栓调节素(THBD)启动的蛋白水解信号通过衰老细胞杀伤减轻年龄相关性肝纤维化。相关论文发表在2023年5月11日出版的《细胞》杂志上。

他们确定THBD信号是衰老细胞命运的关键分子决定因素。虽然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在衰老程序的所有阶段都迅速上调和维持。在机制上，THBD通过稳定早期核内体中的多蛋白复合物激活蛋白水解前馈信号通路，从而为衰老程序的不可逆性形成分子基础，确保衰老细胞的生存能力。在治疗上，在肝纤维化模型中，使用FDA批准的药物vorapaxar减少或抑制THBD信号，可以有效地消融衰老细胞并恢复组织稳态。

总的来说，这些结果揭示了蛋白水解THBD信号作为一个保守的促生存途径对于衰老细胞活力至关重要，从而为衰老相关疾病提供了一个药理学上可利用的衰老靶点。

据了解，细胞衰老是一种应激诱导的、稳定的细胞周期阻滞表型，它产生促炎微环境，导致慢性炎症和年龄相关疾病。确定驱动衰老而非细胞凋亡的基本分子途径，可以鉴定出能够恢复组织稳态的抗衰老药物。

附：英文原文

Title: Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing

Author: Pan, Christopher C., Maeso-Daz, Raquel, Lewis, Tylor R., Xiang, Kun, Tan, Lianmei, Liang, Yaosi, Wang, Liuyang, Yang, Fengrui, Yin, Tao, Wang, Calvin, Du, Kuo, Huang, De, Oh, Seh Hoon, Wang, Ergang, Lim, Bryan Jian Wei, Chong, Mengyang, Alexander, Peter B., Yao, Xuebiao, Arshavsky, Vadim Y., Li, Qi-Jing, Diehl, Anna Mae, Wang, Xiao-Fan

Issue&Volume: 2023-05-11

Abstract: 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.

DOI: 10.1038/s41422-023-00820-4

Source: https://www.nature.com/articles/s41422-023-00820-4