Moon SJ, et al. - A total of 344 skin samples of 173 subjects were studied to analyze the pathways and biomarkers correlated with skin fibrosis using gene-set enrichment analysis. They recognized 1089 upregulated differentially expressed genes (DEGs) including 14 known genetic risk factors and 5 potential drug targets. They observed 4 different clusters of subjects with systemic sclerosis (SSc) with discrete activity signatures for SSc-relevant pathways in the pathway-based subgrouping. They noted both, the closest correlation and temporal pattern to skin fibrosis score in the phosphoinositide-3-kinase-protein kinase B (PI3K-Akt) signaling pathway. They reported COMP, THBS1, THBS4, FN1, and TNC, the leading-edge genes of the PI3K-Akt pathway in skin fibrogenesis. They suggested that the PI3K-Akt pathway and its leading players were promising therapeutic targets.