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Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing
Christopher C Pan 1, Raquel Maeso-Díaz 2, Tylor R Lewis 3, Kun Xiang 1, Lianmei Tan 1, Yaosi Liang 1, Liuyang Wang 4, Fengrui Yang 5, Tao Yin 1, Calvin Wang 1, Kuo Du 2, De Huang 1, Seh Hoon Oh 2, Ergang Wang 1, Bryan Jian Wei Lim 6, Mengyang Chong 1, Peter B Alexander 1, Xuebiao Yao 5, Vadim Y Arshavsky 1 3, Qi-Jing Li 6, Anna Mae Diehl 2, Xiao-Fan Wang 7
...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.