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

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

机构地区：[1]Department of Pharmacology and Cancer Biology,Duke University,Durham,NC,USA [2]Division of Gastroenterology,Department of Medicine,Duke University,Durham,NC,USA [3]Division of Ophthalmology,Department of Medicine,Duke University,Durham,NC,USA [4]Department of Molecular Genetics and Microbiology,Duke University,Durham,NC,USA [5]Department of Physiology,Morehouse School of Medicine,Atlanta,GA,USA [6]Department of Immunology,Duke University,Durham,NC,USA

出　　处：《Cell Research》2023年第7期516-532,共17页细胞研究（英文版）

基　　金：supported by grants from National Institutes of Health(R01CA244564 to X.F.W.,R01DK077794 to A.M.D.);Duke Eye Center EM Facility Core(P30EY005722 to V.Y.A.);NIH Pathway to Independence Award(K99EY033763 to T.R.L.);Florence McAlister Professorship of Medicine(A.M.D.).

摘　　要：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.

关 键 词：homeostasis initiated IRREVERSIBLE 

分 类 号：Q2[生物学—细胞生物学]