A Nutrient-Sensitive O-GlcNAc Switch on RIPK1 Controls Necroptosis and Tissue Homeostasis

Abstract How cells couple metabolic status to programmed cell death remains a fundamental question in biology. Here, we report an O-GlcNAc-based metabolic checkpoint coupling glucose availability to RIPK1-dependent necroptosis. In patients with severe drug-induced skin eruptions, proteomic and metabolomic analyses of patients’ skin lesions revealed markedly decreased O-GlcNAc transferase (OGT) levels, altered levels of hexosamine biosynthesis pathway (HBP) metabolites, and the downregulation of glucose transporters. Mechanistically, OGT-mediated O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) of RIPK1 at Ser331 maintains K63-linked ubiquitination at Lys377, which supports the formation of cytoprotective complexes (RIPK1/FADD/caspase-8) and limits the RIPK1–RIPK3 interaction. Loss of this modification enhances binding to the deubiquitinase CYLD, reduces K63 ubiquitination, and drives keratinocyte necroptosis. In an SJS/TEN animal model, pharmacological inhibition of O-GlcNAcase (OGA) with Thiamet G or PugNAc restored RIPK1 O-GlcNAcylation, attenuated skin pathology, and normalized systemic metabolic abnormalities. Conversely, OGT inhibition or a RIPK1 Ser331- mimetic peptide exacerbated disease. Collectively, our findings define a nutrient-sensitive post-translational checkpoint that integrates glucose metabolism with cell death and tissue homeostasis, with broad implications for inflammatory and metabolic disorders.