NOX4 and neoplasm: Interestingly, BRAFV600E-positive tumors are often associated with a significant decrease or a complete loss of NIS expression, responsible for the resistance of this type of tumor to radioiodine treatment, which may occur via two potential mechanisms: (1) BRAF-induced TGF-β1 represses NIS gene expression through Smad3, a NOX4-dependent downstream pathway; (2) ROS, deriving from NOX4 upregulation, induces Smad3 to inhibit PAX8, the major regulator of NIS transcription, through redox-sensitive epigenetic modifications [123,125], namely, hypermethylation of the NIS promoter [126].