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

Christopher C. Pan¹ , Raquel Maeso-Díaz² , Tylor R. Lewis³ , Kun Xiang¹ , Lianmei Tan¹ , Yaosi Liang¹ , Liuyang Wang⁴ , Fengrui Yang⁵ , Tao Yin¹ , Calvin Wang¹ , Kuo Du² , De Huang¹ , Seh Hoon Oh² , Ergang Wang¹ , Bryan Jian Wei Lim⁶ , Mengyang Chong¹ , Peter B. Alexander¹ , Xuebiao Yao⁵ , Vadim Y. Arshavsky^1,3 , Qi-Jing Li⁶ , Anna Mae Diehl² , Xiao-Fan Wang^1,*

¹Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
²Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA
³Division of Ophthalmology, Department of Medicine, Duke University, Durham, NC, USA
⁴Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA
⁵Department of Physiology, Morehouse School of Medicine, Atlanta, GA, USA
⁶Department of Immunology, Duke University, Durham, NC, USA
* Correspondence: Xiao-Fan Wang(xiao.fan.wang@duke.edu)

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.

https://doi.org/10.1038/s41422-023-00820-4

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