Single-cell RNA sequencing and proteomics uncover glycolytic dysregulation linking skin and systemic inflammation in dermatomyositis

BACKGROUND: Dermatomyositis is a systemic autoimmune disease characterized by progressive muscle weakness and distinctive cutaneous manifestations. While skin involvement is a major clinical feature, the precise cellular and molecular landscape of lesional skin remains poorly defined, limiting our understanding of disease pathogenesis and targeted therapeutic development. OBJECTIVES: To define the systemic and skin lesion landscape of dermatomyositis inflammation, and investigate the underlying pathogenic mechanisms. METHODS: We performed single-cell RNA sequencing (scRNAseq) on skin lesions from adults with classic dermatomyositis in order to construct a high-resolution atlas of the lesional microenvironment. Intercellular communication and trajectory analyses were performed to identify pathogenic cell subpopulations. Proteomic and transcriptomic profiling were integrated to quantify the systemic inflammation burden. Therapeutic validation was conducted in experimental autoimmune myositis (EAM) mouse models. RESULTS: Our study uncovered a unique pathogenic landscape in dermatomyositis, identifying fibroblasts as the dominant signallers, whereas macrophages were dominant in healthy control skin. We characterized a distinct inflammatory fibroblast subset and established type I interferon (IFN-I) signalling 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. CONCLUSIONS: The scRNAseq atlas of dermatomyositis skin lesions delineates a pathogenic cascade centred on inflammatory fibroblasts. We have established the IFN-I signalling pathway and a CXCL10-glycolysis axis as core mechanisms underlying inflammation in dermatomyositis. Therapeutic targeting of glycolytic pathways with 2DG significantly attenuated inflammation in vivo, suggesting potential therapeutic strategies for dermatomyositis.