scRNA-seq and Proteomics Uncover Glycolytic Dysregulation Linking Skin and Systemic Inflammation in Dermatomyositis

Abstract Objective To define the systemic and skin lesion landscape of dermatomyositis (DM) inflammation and investigate pathogenic mechanisms. Methods We performed single-cell RNA sequencing (scRNA-seq) on skin lesions from classic adult dermatomyositis patients to construct a high-resolution atlas of the lesional microenvironment. Intercellular communication and trajectory analysis were performed to identify pathogenic cell subpopulations. Proteomic and transcriptomic profiling were integrated to quantified systemic inflammation burden. Therapeutic validation was conducted in experimental autoimmune myositis (EAM) mouse models. Results Our study uncovered a unique pathogenic landscape in DM skin, identifying fibroblasts as the dominant signaling senders in DM, whereas macrophages served this role in healthy controls. We characterized a distinct inflammatory fibroblast subset and established type I interferon (IFN-I) signaling as a key immune hallmark. Multi-omics integration revealed aberrant CXCL10 expression with heightened glycolysis as a central inflammatory driver. Therapeutic targeting using the glycolysis inhibitor 2-deoxy-D-glucose (2DG) significantly ameliorated inflammation in EAM mice. Conclusion The scRNA-seq atlas of DM skin lesions delineates a pathogenic cascade centered on inflammatory fibroblast. We establish the IFN-I signaling pathway and a CXCL10-glycolysis axis as core mechanisms underlying DM inflammation. Therapeutic targeting of glycolytic pathways with 2DG significantly attenuated inflammation in vivo, suggesting potential therapeutic strategies for DM.