Mechanistically, stiff substrates downregulate the Piezo1 channel expression and thereby reduces Piezo1 channel-mediated extracellular Ca2+ influx to restrain an increase in [Ca2+]i, which favors phosphorylation/inactivation of cofilin through attenuating CaN/SSH1-mediated cofilin dephosphorylation and facilitates filopodia formation, leading to lung cancer cell migration on stiff substrates. This evidence concerns the gene CFL1 and lung cancer.