# Metabolic Reprogramming in Toll-like Receptor-Mediated Platelet Activation

## TL;DR

This study shows how platelet metabolism changes during immune activation and suggests targeting metabolism as a new way to treat inflammation-related diseases.

## Contribution

The study reveals that TLR1/TLR2 activation reprograms platelet metabolism via CD36 and hexokinase, offering a novel therapeutic strategy.

## Key findings

- TLR1/TLR2 activation increases glycolysis in platelets through CD36-linked mechanisms.
- Hexokinase is essential for glycolytic flux and platelet aggregation in TLR1/TLR2 stimulation.
- Targeting platelet metabolic plasticity could inhibit platelet function in TLR-driven diseases.

## Abstract

Beyond haemostasis and thrombosis, platelets are increasingly recognized for playing a crucial role in modulating immunoinflammation. Toll-like receptors (TLRs) constitute the first line of defence against infection and injury, with their engagement stimulating thrombotic and immune responses in platelets. Hence, anti-platelet drugs have been used to treat patients with infections and inflammation. However, due to the increased risk of bleeding with current anti-platelet drugs, alternative therapeutic targets need to be identified to ameliorate the consequences of inflammation-driven platelet hyperactivation. Previously, we demonstrated that resting platelets exhibit a metabolic plasticity that facilitates fuel selection flexibility, while in contrast, thrombin-stimulated platelets become highly glycolytic. Since multiple aspects of platelet activation require energy in terms of ATP, we investigated metabolic alterations in TLR1/TLR2-activated platelets. In this study, we have demonstrated that TLR1/TLR2-induced platelet activation reprogrammed platelets to upregulate glycolysis via CD36-linked mechanisms. In addition, we showed that this glycolytic flux is controlled by hexokinase (HK), which plays a crucial role in TLR1/TLR2-induced platelet aggregation. Targeting platelet metabolism plasticity may offer a novel strategy to inhibit platelet function in TLR-initiated diseases.