Schematic representation of the proposed signaling mechanisms involved in HNE-induced TF decryption. Oxidative stress causes lipid peroxidation and produces reactive aldehydes, such as HNE. HNE induces ROS generation in mitochondria, and ROS increase PS levels in the outer leaflet. Increased PS levels at the outer leaflet contribute to TF decryption. At present, the mechanism by which ROS increase PS levels is unknown. HNE, in addition to generating ROS, also inactivates the TrxR/Trx system by inhibiting its activity or forming adducts. Inhibition of Trx leads to dissociation of the Trx–ASK-1 complex, leading to ASK-1 activation. ASK-1 activation promotes the activation of MKK3/MKK6 and the upstream activation of p38 MAPK. p38 MAPK activation leads to inhibition of flippase activity and a resultant increase in PS levels at the outer leaflet, which contributes to TF activation. HNE-induced TF decryption can be inhibited using specific inhibitors that target different steps in the HNE-induced signaling pathway.