The SAFE pathway for cardioprotection: is this a promising target?

The survivor activating factor enhancement (SAFE) pathway was discovered as an alternative intrinsic pro-survival signaling pathway to the reperfusion injury salvage kinase pathway for cardioprotection against ischemia–reperfusion injury. The delineation of this pathway, made of key components such as cytokines of the immune system and transcription factors, has brought major advancements in our understanding on how the heart is able to protect itself against ischemia–reperfusion injury. In this viewpoint, we describe the major steps leading to the discovery of the SAFE pathway in small animal models to date and we discuss its translation to large animals and humans.