FLI1-Dependent Multicellular Reprogramming in Systemic Sclerosis: From Disease Susceptibility to Organ Pathology

Systemic sclerosis (SSc) combines fibrosis, vasculopathy, and immune dysregulation, but how abnormalities across cellular compartments integrate remains incompletely understood. Reduced FLI1 expression has been reported in several SSc-relevant compartments, through inherited, epigenetic, and signaling-dependent mechanisms demonstrated in specific settings. Experimental perturbation reveals lineage-dependent reprogramming: fibroblasts acquire profibrotic features, endothelial cells lose vascular homeostatic identity, epithelial perturbation produces activation and tolerance-related abnormalities, and B-lineage loss alters development and subset distribution, with dendritic-cell and myeloid findings providing supporting evidence. Lineage-targeted loss demonstrates phenotypic capacity, partial Fli1 reduction sensitizes to additional injury, and combined Klf5/Fli1 insufficiency supports cooperative susceptibility. These states may converge on fibrotic, vascular, and immune disease modules, although the complete network has not been reconstructed and human organ tropism remains unexplained. FLI1 is therefore best viewed as a multicellular susceptibility and phenotype-shaping factor whose effects depend on lineage, dosage, context, and cooperating abnormalities.