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Cyclosporine-A (CsA)-induced gingival overgrowth may arise from an alteration in stoma matrix homeostasis. Sonic hedgehog (Shh) plays a key role during embryogenic development and fibrotic progression, and may be involved in CsA-altered gingival matrix homeostasis.Using the reverse transcription–polymerase chain reaction and Western blot analysis, we investigated the mRNA and protein expressions of Shh, type 1 collagen (COL1), alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) in human gingival fibroblasts after CsA treatments. The effect of Shh on CsA-induced alterations was further evaluated by the extra-supplement or inhibition of Shh or TGF-β.Cyclosporine-A enhanced COL1, α-SMA, Shh and TGF-β expressions in human gingival fibroblasts. The exogenous Shh/TGF-β augmented the expression of COL1 and α-SMA, and the Shh/TGF-β inhibition suppressed the CsA-enhanced COL1 and α-SMA expressions. Moreover, Shh mRNA and protein expressions increased if extra-supplementing the exogenous TGF-β, whereas the CsA-upregulated Shh was mitigated by the TGF-β pathway inhibitor. However, neither exogenous Shh nor the Shh pathway inhibitor alters TGF-β expression or CsA-up-regulated TGF-β expression.Shh, regulated by TGF-β, mediates CsA-altered gingival matrix homeostasis.