The proposed mechanism of FGF-6 in the regulation of hepcidin expression and iron concentrations. Paracrine FGF-6 interacts with FGFR with heparin or heparin sulfate proteoglycan (HPSG) as the cofactor to initial FGF pathway.⁵⁹  Activated FGFRs have the ability to phosphorylate specific tyrosine residues and activate STAT3 pathway.⁶⁰  Iron overload and inflammation could positively regulate hepcidin by BMP/Smad pathway⁶¹  and inflammatory IL-6/STAT3 pathways.^62,63  However, loss-of-function FGF6 variants will silence the FGF6-FGFR pathway, increase free heparin, and reduce expression of hepcidin, thereby decreasing the inhibition of ferroportin-mediated iron transfer from the intracellular compartment to the blood (ie, increasing plasma levels of iron). In SSc patients, IL-6 is increased so that hepcidin will be positively regulated which suppresses iron release to the plasma generating higher iron levels in skin cells.