Ferroptosis is Involved in the Development of Severe Cutaneous Adverse Reactions through xCT/GPX4 Signaling Axis

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug reactions of uncertain pathogenesis. Ferroptosis is an emerging, iron-dependent mode of regulated cell death. However, the correlation between SJS/TEN and ferroptosis has not been elucidated. The purpose of this study is to investigate the relationship between SJS/TEN and ferroptosis. Methods: Proteomic profiling of plasma proteins and imbalance of iron homeostasis of SJS/TEN patients are accompanied with high level of High Mobility Group Box 1 (HMGB1). Glutathione peroxidase 4 (GPX4) and system xc- (xCT) levels were detected by quantitative Polymerase Chain Reaction (qPCR) and Western blot. The morphology of cells was also observed by an electron microscope. Results: The increased serum iron in SJS/TEN patients and mitochondrial morphological alteration further suggested a link between ferroptosis and SJS/TEN. Compared with healthy control, the expressions of xCT, glutathione (GSH), and GPX4 were decreased in SJS/TEN patients, p < 0.05. Additionally, the results of validation experiment in vitro with blister fluids from SJS/TEN patients were also consistent. The expression levels of xCT (p < 0.05) and GPX4 (p < 0.001) were reduced after treatment with erastin and blister fluids, while this phenomenon was reversed by pretreatment with Ferrostatin-1 (Fer-1). Most importantly, we found that the serum concentration of ferritin showed a positive clinical correlation with the severity of drug eruption and the high scoring of severity-of-illness score for TEN (SCORTEN). Conclusions: The overall results show that ferroptosis is involved in the development of SJS/TEN and can be used as a potential target for therapeutic treatment.