Beyond the NFAT Horizon: From Cyclosporine A-Induced Adverse Skin Effects to Novel Therapeutics

The immunophilin ligand, cyclosporine A (CsA), which inhibits nuclear factor of activated T cells (NFAT) activity, is a cornerstone of immunosuppressive therapy. Yet, the molecular basis of its prominent, nonimmunosuppression-related adverse skin effects, namely drug-induced excessive hair growth (hypertrichosis), is insufficiently understood. Here, we argue that analysis of these adverse effects can uncover clinically important, previously unknown mechanisms of CsA and identify new molecular targets and lead compounds for therapeutic intervention. We exemplify this through our recent discovery that CsA suppresses the potent Wnt inhibitor, secreted frizzled related protein (SFRP)1, in human hair follicles, thereby promoting hair growth and causing hypertrichosis. On this basis, we advocate a new focus on deciphering the molecular basis of the adverse effects of CsA in suitable human model systems as a lead to developing novel therapeutics.