TGFβ-activated skin fibroblasts from healthy controls and SSc patients exhibit changes in key regulatory enzymes of energy metabolism and mitochondrial dysfunction (e.g. HIF1alpha, PGC-1alpha). Observed dysregulations of TCA cycle metabolites could influence the activity of epigenetic enzymes (e.g. JMJD3) utilizing metabolic co-factors and lead to pro-fibrotic activation.
Metabolic perturbations caused by extrinsic addition of metabolite dimethyl-alpha ketoglutarate (aKG) and diethyl succinate affected the activity of the JMJD3-mediated H3K27me3, resulting in different expression of profibotic targets (e.g. collagen I, alpha-smooth muscle actin).