Cellular memory of sub-lethal stress

Regulated cell death-processes such as apoptosis, pyroptosis, necroptosis, and ferroptosis-is essential for development, tissue homeostasis, and response to infection or cellular stress. The proteins involved in regulated cell death necessarily possess powerful and potentially damaging activities, including proteolysis, membrane pore formation, DNA cleavage, and inflammatory pathway activation. Traditionally, these activities drive cell death. However, sub-lethal activation of these pathways possesses the potential to promote sustained inflammation, senescence, or oncogenic transformation. Here, we discuss the idea that sub-lethal activation of the cell's intrinsic death programs-rather than the external stresses that initiate these programs-may represent a key mediator of long-term tissue change, with implications for chronic inflammation, aging, and tumorigenesis.