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

## TL;DR

This study shows that a protein called Rubicon in platelets can reduce stroke damage without causing excessive bleeding, offering a new treatment strategy.

## Contribution

The study reveals Rubicon's novel bidirectional regulation of platelet signaling and its therapeutic potential in stroke.

## Key findings

- Rubicon deficiency worsens stroke and bleeding outcomes in mice.
- A Rubicon-Btk peptide reduces cerebral infarction in a mouse model.
- Platelet Rubicon stabilizes thrombi via αIIbβ3 and inhibits GPVI signaling.

## 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.

This study identifies Rubicon as a key platelet protein that bidirectionally regulates GPVI and integrin αIIbβ3 signaling. Platelet Rubicon protects against cerebral ischemia‐reperfusion injury by limiting infarction without increasing hemorrhage. A cell‐penetrating peptide mimicking Rubicon function reduces ischemic injury, presenting a novel therapeutic strategy for stroke.