Exosomal miR-375-3p mediated lipid metabolism, ferritinophagy and CoQ-dependent pathway contributes to the ferroptosis of keratinocyte in SJS/TEN.

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) manifest life-threatening cutaneous adverse drug reactions characterized by keratinocyte death. Previous studies have indicated that apoptosis and necroptosis are implicated in SJS/TEN pathogeneses. However, other forms of cell death involved in this process remain unidentified. Ferroptosis, cell death driven by iron-dependent lipid peroxidation, has been implicated in various human diseases. In this study, the identification of ferroptosis and the potential effects of ferroptosis on SJS/TEN were investigated. We demonstrated that the skin lesions and plasma of SJS/TEN patients show increased levels of lipid peroxidation and iron. The biomarkers of ferroptosis correlated positively with the disease severity in SJS/TEN patients. Besides, plasma exosomes derived from patients with SJS/TEN exhibited elevated levels of cellular oxidized polyunsaturated fatty acids (PUFAs) and phospholipids phosphatidylethanolamine (PE), the key phospholipids that drive cells towards ferroptotic death. miR-375-3p, enriched in plasma-derived exosomes from SJS/TEN patients, was observed reduce both ferritin heavy chain 1 (FTH1) and ferroptosis suppressor protein 1 (FSP1) expression. Parallelly, exosomal miR-375-3p overexpression increased the level of lipid peroxidation but decreased the coenzyme Q10 (CoQ10), thus enhancing the ferroptosis rate of keratinocyte. Above all, we concluded that ferritinophagy-mediated ferroptosis, lipid metabolism, and the FSP1-CoQ-dependent pathway in ferroptosis are critical mechanisms contributing to SJS/TEN. Targeting ferroptosis in keratinocyte may be a therapeutic strategy for preventing SJS/TEN in the future.