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.
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The RNA transcriptional profiling data involved in this study has been uploaded to NCBI GEO datasets (GSE228941).
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We thank Dr. Tso-Pan Yao and Dr. Nina Tsvetanova for their valuable insight and discussion on endosomal dynamics and signaling. We also thank Drs. Rui Chen, Handan Xiang, Yi Ding, and Omar Lopez for their extensive discussion and valuable input on the senescent field.
This work was 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.).
The authors declare no competing interests.
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Pan, C.C., Maeso-Díaz, R., Lewis, T.R. et al. Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing. Cell Res 33, 516–532 (2023). https://doi.org/10.1038/s41422-023-00820-4
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