Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced cutaneous reactions characterized by keratinocyte cell death1. Ferroptosis is a recently recognized form of regulated cell death driven by lipid-based reactive oxygen species (ROS) accumulation2. However, the molecular mechanisms of ferroptosis regulation are still largely unknown in SJS/TEN. Exosomes are nanometer-sized membranous vesicles in body fluids. They contain functional proteins, DNA, mRNAs and miRNAs, influence disease progress3. However, their mechanisms in ferroptosis of SJS/TEN remain unknown. Exosomes isolated from SJS/TEN plasma were 30–200 nm in diameter and expressed CD9, CD63, CD81, and TSG101 marker proteins. The results demonstrated that miR-375-3p was markedly upregulated in 40 SJS/TEN patients and positively correlated with clinical severity. Then, plasma derived exosomes from patients were internalized by human primary keratinocytes and increased free iron, lipid peroxidation, and malondialdehyde (MDA) accumulation, all of which are important hallmarks of ferroptosis. Additionally, ectopic expression of miR-375-3p suppressed glutathione peroxidase 4 (GPX4), an enzyme crucial in converting toxic lipid hydroperoxides to nontoxic lipid alcohols, resulting in increased ferroptotic cell death. Interestingly, ferroptotic cell death augmented pancreas islet β cell dysfunction and increased glucose level. Our study firstly shows that exosomal miR-375-3p enters keratinocytes, downregulates GPX4, induces keratinocyte ferroptosis and augments pancreas islet β cell dysfunction in SJS/TEN patients, and may serve as a marker of SJS/TEN pathology.

Plasma exosomal miR-375-3p regulates ferroptosis in keratinocytes by targeting GPX4 in SJS/TEN