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Oral submucous fibrosis (OSF) caused by areca nut chewing is a prevalent fibrotic disease in Asia‐Pacific countries. Arecoline‐induced migration of fibroblasts (FBs) plays a vital role in the development of OSF. However, the specific molecular mechanisms involved remain unclear. Many studies have shown that tyrosine sulphation of chemokines can influence cell migration. Herein, we demonstrated that arecoline stimulates tyrosine sulphation of the chemokine receptor 4 (CXCR4) through the tyrosylprotein sulphotransferase‐1 (TPST‐1) to enhance the migration ability of FBs. Moreover, by RNA‐Seq analysis, we found that the most significantly altered pathway was the EGFR pathway after the arecoline stimulation for FBs. After the knockdown of arecoline‐induced EGFR expression, the tyrosine sulphation of CXCR4 was significantly decreased by the inhibition of TPST‐1 induction. Finally, in human OSF specimens, TPST‐1 expression was directly correlated with the expression of CXCR4. These data indicate that the arecoline‐induced tyrosine sulphation of CXCR4, which is regulated by TPST‐1, might be a potential mechanism that contributes to FB migration in OSF. [ABSTRACT FROM AUTHOR]