It is well established that cytosolic caspase-1 activation, mediated by inflammasome after pathogens-associated molecular patterns (PAMP) and metabolic danger-associated molecular patterns (DAMPs), mediates the initiation of inflammation in endothelial cells by its downstream targets such as Interleukin-1β (IL-1β), Interleukin-18 (IL-18), and Sirtuin-1. However, it remains unknown whether proatherogenic lipids lysophosphatidylcholine (LPC) and reactive oxygen species (ROS) can promote nuclear localization of caspase-1. Using biochemical, bioinformatic, and immunologic approaches, we made the following findings: (1) DNA damage was found in atherosclerotic mice. (2) A nuclear exportation signal was mapped in the CARD domain of pro-caspase-1. LPC promotes nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs), which may interrupt DNA damage and repair pathways. (3) Blockage of caspase-1 nuclear cytosol trafficking in HAEC activated by LPC may mediate inflammation and interrupt cell cycle regulation. (4) Pro-caspase-1 in the nucleus inhibits inflammation but promotes interferon pathways. Activation of caspase-1 in the nucleus promotes aging- and fos-related antigen 2 (FRA2) mediated DNA damage and apoptosis. (5) Inhibition of SUMOylation decreases pro-caspase-1 translocation into the cytosol from the nucleus. (6) Blockage of caspase-1 cytosol nuclear trafficking in HAEC activated by H2O2 may decrease caspase-1 activity and increase cell viability. Our results demonstrate, for the first time, that caspase-1 patrols in the cell, senses danger signals and interrupts the balance between DNA damage and DNA repair pathways. It is a novel insight that not only should we suppress the inflammation in the cytosol but also in the nucleus, which is important for the future development of therapeutics for cardiovascular diseases and other inflammatory diseases. / Biomedical Sciences