Platelet ferroptosis promotes oxidized mtDNA release and SLE progression

Background: 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. Methods: 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 or vehicle and the severity of lupus disease was assessed. Results: Platelets of SLE patients showed lower expression of GPX4 than that of healthy controls. The expression of GPX4 in SLE platelets was negativelycorrelated with disease activity and plasma oxidized DNA. SLE platelets with low expression of GPX4 were highly activated and susceptible to ferroptosis and resulting in elevated release of oxidized DNA. In vitro, GPX4 inhibitor induced ferroptosis and oxidized DNA release from healthy control platelets, whereas the GPX4 activator protected SLE platelets from ferroptosis and inhibited the release of oxidized DNA. In MRL/ lpr mice, treatment of GPX4 activator alleviated lupus-like features, inhibited platelet ferroptosis and reduced the release of oxidized DNA. Conclusions: These findings demonstrate that 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.