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

Publication ,  Journal Article
Pan, CC; Maeso-Díaz, R; Lewis, TR; Xiang, K; Tan, L; Liang, Y; Wang, L; Yang, F; Yin, T; Wang, C; Du, K; Huang, D; Oh, SH; Wang, E; Yao, X ...
Published in: Cell Res
July 2023

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.

Duke Scholars

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Published In

Cell Res

DOI

EISSN

1748-7838

Publication Date

July 2023

Volume

33

Issue

7

Start / End Page

516 / 532

Location

England

Related Subject Headings

  • Thrombomodulin
  • Signal Transduction
  • Mammals
  • Liver Cirrhosis
  • Endothelial Cells
  • Developmental Biology
  • Cellular Senescence
  • Apoptosis
  • Animals
  • 3101 Biochemistry and cell biology
 

Citation

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Pan, C. C., Maeso-Díaz, R., Lewis, T. R., Xiang, K., Tan, L., Liang, Y., … Wang, X.-F. (2023). Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing. Cell Res, 33(7), 516–532. https://doi.org/10.1038/s41422-023-00820-4
Pan, Christopher C., Raquel Maeso-Díaz, Tylor R. Lewis, Kun Xiang, Lianmei Tan, Yaosi Liang, Liuyang Wang, et al. “Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.Cell Res 33, no. 7 (July 2023): 516–32. https://doi.org/10.1038/s41422-023-00820-4.
Pan CC, Maeso-Díaz R, Lewis TR, Xiang K, Tan L, Liang Y, et al. Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing. Cell Res. 2023 Jul;33(7):516–32.
Pan, Christopher C., et al. “Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.Cell Res, vol. 33, no. 7, July 2023, pp. 516–32. Pubmed, doi:10.1038/s41422-023-00820-4.
Pan CC, Maeso-Díaz R, Lewis TR, Xiang K, Tan L, Liang Y, Wang L, Yang F, Yin T, Wang C, Du K, Huang D, Oh SH, Wang E, Lim BJW, Chong M, Alexander PB, Yao X, Arshavsky VY, Li Q-J, Diehl AM, Wang X-F. Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing. Cell Res. 2023 Jul;33(7):516–532.

Published In

Cell Res

DOI

EISSN

1748-7838

Publication Date

July 2023

Volume

33

Issue

7

Start / End Page

516 / 532

Location

England

Related Subject Headings

  • Thrombomodulin
  • Signal Transduction
  • Mammals
  • Liver Cirrhosis
  • Endothelial Cells
  • Developmental Biology
  • Cellular Senescence
  • Apoptosis
  • Animals
  • 3101 Biochemistry and cell biology