METABOLIC reprogramming in the skin may fuel systemic inflammation in patients with dermatomyositis (DM), according to a new study, opening potential paths to novel therapies. Researchers used single-cell RNA sequencing and proteomic analysis to dissect the cellular landscape of DM skin lesions and link it to broader systemic immune activation.
Systemic Inflammation Rooted in Skin Fibroblasts
By mapping skin samples from adults with DM at single-cell resolution, the team uncovered that fibroblasts, not immune cells, emerge as the main signalling hub within inflamed skin. These so-called “inflammatory fibroblasts” showed strong activation of the type I interferon (IFN-I) pathway, a hallmark of immune dysregulation, and were linked to elevated expression of the chemokine CXCL10.
Importantly, the study identified a novel “CXCL10–glycolysis axis” as a core mechanism driving inflammation. Proteomic and transcriptomic data from both skin and blood suggested that increased glycolytic activity in inflammatory fibroblasts correlates with systemic inflammatory signals. This metabolic shift appears to amplify immune activation beyond the skin, linking local pathology to systemic disease burden.
In a preclinical model of autoimmune myositis, inhibiting glycolysis using 2‑deoxy‑D‑glucose (2DG) significantly reduced inflammation, supporting the idea that metabolic reprogramming is not just a bystander but a driver of disease. These findings suggest that targeting cellular metabolism, particularly glycolysis, might offer a promising new therapeutic avenue for DM.
Implications for Clinical Care and Future Research
The study challenges the traditional view that immune cells are the main culprits in DM skin inflammation, highlighting instead a central role for fibroblasts and metabolic dysfunction. The link between skin-level changes and systemic inflammation underscores the importance of holistic disease management. The authors call for further research into metabolism-targeted treatments and suggest integrating metabolomic and proteomic profiling into routine care to better stratify patients and personalise therapy.
Reference
Xu X et al. scRNA-seq and proteomics uncover glycolytic dysregulation linking skin and systemic inflammation in dermatomyositis. Br J Dermatol. 2025. doi: 10.1093/bjd/ljaf486.
