Platelet ferroptosis promotes oxidized DNA release and SLE progression

Ferroptosis is a recently identified type of regulated necrosis, and glutathione peroxidase 4 (GPX4) has been recognized as a key enzyme that protects against ferroptosis. However, the role of platelet ferroptosis in systemic lupus erythematosus (SLE) has not been explored. This study aimed to investigate the role of GPX4-mediated platelet ferroptosis in SLE.

GPX4 protein expression in platelets was detected by Western blot and immunofluorescence analysis. The correlation of platelet GPX4 expression with SLE clinical characteristics was evaluated. The ability of platelet activation and ferroptosis was detected, and the release of oxidized DNA by platelets was tested. In addition, GPX4 inhibitor and activator were used to evaluate the effect of GPX4 on platelet ferroptosis and oxidized DNA release. Finally, MRL/lpr mice were treated with GPX4 activator 1 or vehicle and the severity of lupus disease was assessed.

Platelets of SLE patients showed lower expression of GPX4, which was negatively correlated with disease activity and plasma oxidized DNA levels. These platelets were more activated, prone to ferroptosis, and released higher levels of oxidized DNA. In vitro, GPX4 inhibitor induced ferroptosis and oxidized DNA release in healthy control platelets, whereas the GPX4 activator 1 protected SLE platelets. In MRL/lpr mice, treatment with GPX4 activator 1 alleviated lupus severity, reduced platelet ferroptosis, and decreased oxidized DNA release.

SLE platelets exhibit low GPX4 expression and are more susceptible to ferroptosis, highlighting the critical role of GPX4 downregulation-mediated platelet ferroptosis in the development of SLE. Therefore, activation of GPX4 may represent a therapeutic strategy for SLE. Key Points • SLE platelets exhibit low GPX4 expression and are more susceptible to ferroptosis and the release of oxidized DNA. • Pharmacological activation of GPX4 inhibits platelet ferroptosis and oxidized DNA release in vitro and in vivo. • Targeting platelet ferroptosis via GPX4 activation alleviates disease severity in MRL/lpr mice.