Previously we reported that NOX4 serves as a glycolytic regulator via ROS in hypoxia [10], the present study demonstrated not only the supportive effect of NOX4 on lenvatinib-induced glycolysis under serum-starved conditions via ROS in PTC cells in vitro, but also the surprising effect upon combinatory treatment of GLX351322 and lenvatinib in vivo, suggesting that PTC cells depend on NOX4 or NOX4-derived ROS to establish plasticity that is capable of responding to complex and changeable tumor microenvironments. Here, NOX4 is linked to neoplasm.