Sublethal Caspase-8 Activation Drives Radiation-Induced Genetic Instability and Oncogenic Transformation Through Endonuclease G and Non-Canonical NF-κB Signaling

Apoptosis is traditionally considered a definitive barrier against oncogenesis, as caspase activation typically eliminates damaged and genetically unstable cells. Here, we report that caspase-8, an initiator of extrinsic apoptosis, paradoxically promotes genetic instability and carcinogenesis following exposure to radiation. We observed that a substantial fraction of mammalian cells exposed to ionizing radiation can survive despite caspase-8 activation. This sublethal activation of caspase-8 facilitated persistent DNA damage, which was attenuated by the expression of a dominant-negative caspase-8 (C360A, Casp8DN) or short hairpin RNA (shRNA)-mediated knockdown of caspase-8 in mammalian cells. The facilitative role of caspase-8 in radiation-induced genomic instability was further validated in caspase-8 heterozygous mice. Moreover, inhibition of caspase-8 abolished iron-ion radiation-induced oncogenic transformation in both soft agar and nude mice. Mechanistically, sublethal caspase-8 activation promoted the nuclear translocation of mitochondrial endonuclease G and persistent DNA damage, accompanied by activation of non-canonical nuclear factor κB (NF-κB) signaling. Collectively, our findings demonstrate that caspase-8 can act as a causative driver of radiation-induced malignancy, challenging the dogma of caspases as universal anticancer barriers and providing important insights into the long-term health risks associated with space radiation and radiotherapy.