Meridianin C is a marine natural product known for its antiâcancer activity. At present, the antiâtumour effects of meridianin C on oral squamous cell carcinoma are unknown. Here, we investigated the effect of meridianin C on the proliferation of four different human tongue cancer cells, YDâ8, YDâ10B, YDâ38 and HSCâ3. Among the cells tested, meridianin C most strongly reduced the growth of YDâ10B cells; the most aggressive and tumorigenic of the cell lines tested. Strikingly, meridianin C induced a significant accumulation of macropinosomes in the YDâ10B cells; confirmed by the microscopic and TEM analysis as well as the entry of FITCâdextran, which was sensitive to the macropinocytosis inhibitor amiloride. SEM data also revealed abundant long and thin membrane extensions that resemble lamellipodia on the surface of YDâ10B cells treated with meridianin C, pointing out that meridianin Câinduced macropinosomes was the result of macropinocytosis. In addition, meridianin C reduced cellular levels of Dickkopfârelated proteinâ3 (DKKâ3), a known negative regulator of macropinocytosis. A role for DKKâ3 in regulating macropinocytosis in the YDâ10B cells was confirmed by siRNA knockdown of endogenous DKKâ3, which led to a partial accumulation of vacuoles and a reduction in cell proliferation, and by exogenous DKKâ3 overexpression, which resulted in a considerable inhibition of the meridianin Câinduced vacuole formation and decrease in cell survival. In summary, this is the first study reporting meridianin C has novel antiâproliferative effects via macropinocytosis in the highly tumorigenic YDâ10B cell line and the effects are mediated in part through downâregulation of DKKâ3.