journal article·2026-03Open access

Platelet Rubicon Bidirectional Regulation of GPVI and Integrin αIIbβ3 Signaling Mitigates Stroke Infarction Without Compromising Hemostasis

Xiaoyan Chen, Jingke Li, Yangyang Liu, Li Li, Xin Deng, Yilin Sheng, Xianyu Zhu, Xiao Jiang, Wei Li, Xueli Cai, Qiming Sun, Hu Hu

Advanced Science· Volume 13· Issue 16

Abstract

ABSTRACT Inhibiting the platelet glycoprotein VI (GPVI) receptor is a promising strategy for reducing cerebral ischemia‐reperfusion injury (CIRI) without severe compromise of hemostasis, while targeting glycoprotein IIb/IIIa (integrin αIIbβ3) causes bleeding. The underlying cellular mechanism remains unclear. This study shows that megakaryocyte‐platelet‐specific deficiency of the autophagic protein Rubicon (Run domain protein as Beclin‐1 interacting and cysteine‐rich containing) accelerates stroke development and exacerbates cerebral hemorrhage. Rubicon interacts with Bruton's tyrosine kinase (Btk) to inhibit GPVI‐mediated thrombus formation, while it prevents αIIbβ3‐mediated selective autophagy and degradation of Btk to stabilize platelet thrombi. The expression of Rubicon in platelets is decreased in patients with acute ischemic‐reperfusion injury. A cell‐permeable peptide mimicking the Rubicon‐Btk interaction significantly reduces cerebral infarction volume in a mouse model. As Rubicon is dispensable for hemostasis but crucial in the reperfusion stage of CIRI, peptides mimicking its effects may offer a selective and safe therapeutic strategy.
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Research context

OpenAlex topics: Platelet Disorders and Treatments · Blood Coagulation and Thrombosis Mechanisms · Neutrophil, Myeloperoxidase and Oxidative Mechanisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China

Institute of Hematology Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy Zhejiang University Hangzhou China

Department of Cardiology The First Affiliated Hospital of Zhengzhou University Zhengzhou China

State Key Laboratory of Transvascular Implantation Devices Department of Cardiology of The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou China

Heart Regeneration and Repair Key Laboratory of Zhejiang Province Hangzhou China

Lishui Central Hospital The Fifth Affiliated Hospital of Wenzhou Medical University Lishui Hospital of Zhejiang University Lishui China

Department of Biochemistry and Molecular Biology Zhejiang University School of Medicine Hangzhou China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Zhejiang Province

References (56)

Show source-provided references
1. 10.1177/1060028021107300910.1177/10600280211073009 ↗
2. 10.1038/s41572‐023‐00424‐710.1038/s41572‐023‐00424‐7 ↗
3. 10.1161/CIRCULATIONAHA.107.69127910.1161/CIRCULATIONAHA.107.691279 ↗
4. 10.1016/S1474‐4422(19)30034‐110.1016/S1474‐4422(19)30034‐1 ↗
5. 10.1016/j.cell.2011.10.02610.1016/j.cell.2011.10.026 ↗
6. 10.7554/eLife.2140710.7554/eLife.21407 ↗
7. 10.1111/jpi.1243810.1111/jpi.12438 ↗
8. 10.1152/physiol.00030.201710.1152/physiol.00030.2017 ↗
9. 10.4161/auto.2783210.4161/auto.27832 ↗
10. 10.1182/blood‐2014‐09‐59872210.1182/blood‐2014‐09‐598722 ↗
11. 10.1080/15548627.2021.190449510.1080/15548627.2021.1904495 ↗
12. 10.1161/ATVBAHA.117.30975110.1161/ATVBAHA.117.309751 ↗
13. 10.1182/blood‐2017‐04‐78164110.1182/blood‐2017‐04‐781641 ↗
14. 10.1080/09537104.2018.147563010.1080/09537104.2018.1475630 ↗
15. 10.1182/bloodadvances.201903233410.1182/bloodadvances.2019032334 ↗
16. 10.15252/emmm.20150604610.15252/emmm.201506046 ↗
17. 10.1111/febs.1435410.1111/febs.14354 ↗
18. 10.1074/jbc.M110.12642510.1074/jbc.M110.126425 ↗
19. 10.1172/JCI13236610.1172/JCI132366 ↗
20. 10.1111/jnc.1572110.1111/jnc.15721 ↗
21. 10.1007/s00395‐020‐0790‐610.1007/s00395‐020‐0790‐6 ↗
22. 10.1038/s41419‐022‐04682‐310.1038/s41419‐022‐04682‐3 ↗
23. 10.1016/j.chom.2012.01.01910.1016/j.chom.2012.01.019 ↗
24. 10.1091/mbc.E10‐06‐049510.1091/mbc.E10‐06‐0495 ↗
25. 10.1073/pnas.101055410710.1073/pnas.1010554107 ↗
26. 10.1016/j.chom.2012.01.01810.1016/j.chom.2012.01.018 ↗
27. 10.1128/jvi.00248‐1710.1128/jvi.00248‐17 ↗
28. 10.1042/BJ2007142710.1042/BJ20071427 ↗
29. 10.1002/jcp.104116011610.1002/jcp.1041160116 ↗
30. 10.1038/ncb184610.1038/ncb1846 ↗
31. 10.1042/EBC2017003510.1042/EBC20170035 ↗
32. 10.1161/ATVBAHA.118.31231410.1161/ATVBAHA.118.312314 ↗
33. 10.1016/S1074‐5521(01)00076‐X10.1016/S1074‐5521(01)00076‐X ↗
34. 10.1182/blood‐2003‐03‐071710.1182/blood‐2003‐03‐0717 ↗
35. 10.1161/01.CIR.0000146341.63677.3C10.1161/01.CIR.0000146341.63677.3C ↗
36. 10.1038/ncb185410.1038/ncb1854 ↗
37. 10.1021/bi010078810.1021/bi0100788 ↗
38. 10.1126/science.833290110.1126/science.8332901 ↗
39. 10.1074/jbc.M11039020010.1074/jbc.M110390200 ↗
40. 10.1016/S0021‐9258(17)34048‐610.1016/S0021‐9258(17)34048‐6 ↗
41. 10.1038/ni1001‐93910.1038/ni1001‐939 ↗
42. 10.1074/jbc.M60309020010.1074/jbc.M603090200 ↗
43. 10.1161/ATVBAHA.115.30613010.1161/ATVBAHA.115.306130 ↗
44. 10.1161/CIRCULATIONAHA.110.98062310.1161/CIRCULATIONAHA.110.980623 ↗
45. 10.1182/blood‐2015‐07‐65918510.1182/blood‐2015‐07‐659185 ↗
46. 10.3324/haematol.2021.27977010.3324/haematol.2021.279770 ↗
47. 10.1055/a‐2263‐837210.1055/a‐2263‐8372 ↗
48. 10.1186/2040‐7378‐3‐910.1186/2040‐7378‐3‐9 ↗
49. 10.1016/S0169‐328X(98)00271‐X10.1016/S0169‐328X(98)00271‐X ↗
50. 10.1161/STROKEAHA.119.02665210.1161/STROKEAHA.119.026652 ↗
51. 10.1182/blood.202000891310.1182/blood.2020008913 ↗
52. 10.3791/50062‐v10.3791/50062‐v ↗
53. 10.1074/jbc.M80771920010.1074/jbc.M807719200 ↗
54. Effects of Isoflurane Anesthesia on the Cardiovascular Function of the C57BL/6 Mouse
55. 10.1097/00000539‐199902000‐0003910.1097/00000539‐199902000‐00039 ↗
56. 10.1097/TA.0b013e318184ba7210.1097/TA.0b013e318184ba72 ↗