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Introduction Previous studies identified several subsets of fibroblasts (Fb) in systemic sclerosis (SSc) skin and showed that Fb undergo metabolic reprogramming upon activation. However, metabolic phenotyping of Fb and their niche with single-cell and spatial resolution has not been performed in SSc. We aimed to perform spatially informed single-cell metabolic phenotyping of Fb, macrophages and endothelial cells (EC), as well as of their cellular niches, and evaluate their association with progression of skin fibrosis in SSc, using imaging mass cytometry (IMC).Material and Methods Skin biopsies from nine SSc patients and seven controls were used. An IMC panel of 38 antibodies, 22 of which targeting key metabolic regulators, was designed and validated in human skin. Data analysis was performed as described previously. Of note, glycolysis or the oxidative phosphorylation (OxPhos) scores correlate with the respective pathway activities determined by functional assays.Results We analyzed the expression of key regulators of glycolysis, OxPhos, fatty acid oxidation and synthesis, aminoacid internalization, pentose phosphate pathway, hypoxia, reactive oxygen species and mitochondrial dynamics, collectively termed as metabolic regulome, in SSc and control skin.We identified a distinct metabolic regulome in dermal cells of SSc patients with progressive skin fibrosis compared with patients with stable skin fibrosis and controls, with upregulation of glycolysis and OxPhos scores.Unbiased clustering of Fb identified eight Fb subsets defined by their metabolic regulome. Of these, a subset of Fb with high expression of glycolysis and OxPhos enzymes (termed Methi Fb) was upregulated in SSc patients with progressive skin fibrosis, and expressed high levels of αSMA und FAP. In contrast, a subset of Fb with low expression of glycolysis and OxPhos enzymes (termed Metlow Fb), was downregulated in SSc patients with progressive skin fibrosis.The Fb subsets defined by their metabolic regulome formed niches with EC and macrophages with similar levels of metabolic pathway activities, e.g. the Methi Fb were in spatial proximity to EC and macrophages expressing high levels of glycolysis and OxPhos enzymes.Conclusions Using IMC, we identified distinct subsets of Fb defined by their metabolic profiles in SSc and control skin, with a switch from resting Fb with low metabolic activity to metabolically highly active Fb in progressive skin fibrosis. These Fb with high metabolic activity were expressing myofibroblast markers and were forming niches with other cells with a similar metabolic profile. Thus, metabolic phenotyping of Fb and their niches by IMC might identify SSc patients at risk for progression of skin fibrosis.