Necroptotic cell death consequences and disease relevance.

Arguably one of the most surprising revelations in the field of cell death research was the discovery that cellular necrosis, a lytic and inherently messy cell death with far-reaching consequences for human physiology, can be genetically encoded. There is no single necrotic pathway either, as compelling evidence exists for distinct necrotic modalities such as pyroptosis, necroptosis and ferroptosis. The recent momentum of molecular, structural and disease-relevant findings has opened the door to targeting necrotic machinery to prevent collateral tissue damage and inflammatory diseases. In this Review, we evaluate the case for targeting the necrotic cell death pathway called necroptosis. We examine the organs and cell types where the human necroptotic machinery is expressed, identifying a lymphocytic ZBP1, RIPK1, RIPK3 and MLKL signature, review knowledge into the immunogenic consequences of necroptotic signaling and highlight building evidence that necroptosis is engaged in humans and can be triggered by ischemic injuries. Finally, we note several limitations of mouse studies due to fundamental differences with the human necroptotic apparatus and critically appraise the evidence for necroptosis being a disease-driving factor that, if successfully targeted, could be of clinical benefit.