Volume 33, No 7, Jul 2023
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 33 Issue 7, July 2023: 516-532
Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing
Christopher C. Pan1 , Raquel Maeso-Díaz2 , Tylor R. Lewis3 , Kun Xiang1 , Lianmei Tan1 , Yaosi Liang1 , Liuyang Wang4 , Fengrui Yang5 , Tao Yin1 , Calvin Wang1 , Kuo Du2 , De Huang1 , Seh Hoon Oh2 , Ergang Wang1 , Bryan Jian Wei Lim6 , Mengyang Chong1 , Peter B. Alexander1 , Xuebiao Yao5 , Vadim Y. Arshavsky1,3 , Qi-Jing Li6 , Anna Mae Diehl2 , Xiao-Fan Wang1,*1Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
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.