Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.
| dc.contributor.author | Pan, Christopher C | |
| dc.contributor.author | Maeso-Díaz, Raquel | |
| dc.contributor.author | Lewis, Tylor R | |
| dc.contributor.author | Xiang, Kun | |
| dc.contributor.author | Tan, Lianmei | |
| dc.contributor.author | Liang, Yaosi | |
| dc.contributor.author | Wang, Liuyang | |
| dc.contributor.author | Yang, Fengrui | |
| dc.contributor.author | Yin, Tao | |
| dc.contributor.author | Wang, Calvin | |
| dc.contributor.author | Du, Kuo | |
| dc.contributor.author | Huang, De | |
| dc.contributor.author | Oh, Seh Hoon | |
| dc.contributor.author | Wang, Ergang | |
| dc.contributor.author | Lim, Bryan Jian Wei | |
| dc.contributor.author | Chong, Mengyang | |
| dc.contributor.author | Alexander, Peter B | |
| dc.contributor.author | Yao, Xuebiao | |
| dc.contributor.author | Arshavsky, Vadim Y | |
| dc.contributor.author | Li, Qi-Jing | |
| dc.contributor.author | Diehl, Anna Mae | |
| dc.contributor.author | Wang, Xiao-Fan | |
| dc.date.accessioned | 2023-12-01T17:09:23Z | |
| dc.date.available | 2023-12-01T17:09:23Z | |
| dc.date.issued | 2023-07 | |
| dc.date.updated | 2023-12-01T17:09:22Z | |
| dc.description.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. | |
| dc.identifier | 10.1038/s41422-023-00820-4 | |
| dc.identifier.issn | 1001-0602 | |
| dc.identifier.issn | 1748-7838 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | Springer Science and Business Media LLC | |
| dc.relation.ispartof | Cell research | |
| dc.relation.isversionof | 10.1038/s41422-023-00820-4 | |
| dc.subject | Endothelial Cells | |
| dc.subject | Animals | |
| dc.subject | Mammals | |
| dc.subject | Liver Cirrhosis | |
| dc.subject | Thrombomodulin | |
| dc.subject | Signal Transduction | |
| dc.subject | Apoptosis | |
| dc.subject | Cellular Senescence | |
| dc.title | Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Wang, Liuyang|0000-0001-9556-2361 | |
| duke.contributor.orcid | Du, Kuo|0000-0002-1446-4653 | |
| duke.contributor.orcid | Lim, Bryan Jian Wei|0000-0002-6048-2609 | |
| duke.contributor.orcid | Arshavsky, Vadim Y|0000-0001-8394-3650 | |
| duke.contributor.orcid | Li, Qi-Jing|0000-0002-0542-9784 | |
| pubs.begin-page | 516 | |
| pubs.end-page | 532 | |
| pubs.issue | 7 | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Student | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Cell Biology | |
| pubs.organisational-group | Integrative Immunobiology | |
| pubs.organisational-group | Molecular Genetics and Microbiology | |
| pubs.organisational-group | Pharmacology & Cancer Biology | |
| pubs.organisational-group | Medicine | |
| pubs.organisational-group | Ophthalmology | |
| pubs.organisational-group | Medicine, Gastroenterology | |
| pubs.organisational-group | Ophthalmology, Vitreoretinal Diseases & Surgery | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Institutes and Provost's Academic Units | |
| pubs.organisational-group | University Institutes and Centers | |
| pubs.organisational-group | Duke Institute for Brain Sciences | |
| pubs.organisational-group | Regeneration Next Initiative | |
| pubs.publication-status | Published | |
| pubs.volume | 33 |
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