In accordance with earlier research that found that arecoline induces oral submucous fibrosis through activation of the TGF-β1/Smad signaling pathway, our data provided show that the i.p. administration of arecoline significantly increased the protein expression levels of fibrotic modulators, including TGF-β1, p-Smad2/3, SP1, and CTGF. The gene discussed is CCN2; the disease is oral submucous fibrosis.