Platelet ferroptosis promotes oxidized DNA release and SLE progression

Area of Science:

• Immunology
• Cell Biology
• Pathology

Background:

• Ferroptosis is a regulated necrosis pathway.
• Glutathione peroxidase 4 (GPX4) is a key enzyme protecting against ferroptosis.
• The role of platelet ferroptosis in systemic lupus erythematosus (SLE) remains unexplored.

Purpose of the Study:

• To investigate the role of GPX4-mediated platelet ferroptosis in SLE.
• To explore the potential of GPX4 activation as a therapeutic strategy for SLE.

Main Methods:

• Assessed GPX4 protein expression in platelets from SLE patients and healthy controls using Western blot and immunofluorescence.
• Evaluated the correlation between platelet GPX4 expression and SLE clinical characteristics.
• Measured platelet activation, ferroptosis, and oxidized DNA release.
• Utilized GPX4 inhibitors and activators in vitro.
• Administered GPX4 activator 1 to MRL/lpr mice to assess lupus severity.

Main Results:

• SLE platelets exhibited lower GPX4 expression, negatively correlated with disease activity and plasma oxidized DNA levels.
• SLE platelets were hyperactivated, prone to ferroptosis, and released more oxidized DNA.
• GPX4 inhibition induced ferroptosis and oxidized DNA release in healthy platelets; GPX4 activation protected SLE platelets.
• GPX4 activator 1 treatment alleviated lupus severity in MRL/lpr mice, reducing platelet ferroptosis and oxidized DNA release.

Conclusions:

• Downregulation of GPX4 in SLE platelets promotes ferroptosis and oxidized DNA release, contributing to SLE pathogenesis.
• Pharmacological activation of GPX4 demonstrates therapeutic potential by inhibiting platelet ferroptosis and alleviating lupus severity in vivo.
• Targeting platelet ferroptosis via GPX4 activation represents a promising therapeutic strategy for SLE.