Mitogen-activated protein kinase kinase kinase 4 (MEKK4) and Kruppel-like transcription factors (KLF) are both known targets and regulators of redox signaling53–55, as is Toll-like receptor 4 (TLR4)56, suggesting that ROS signaling may also be involved in the MEKK4/KLF4/TLR4 signaling axis recently identified as important in CCM pathogenesis57, 58. This evidence concerns the gene MAPK4 and cerebral cavernous malformation.