IFI16-mediated cellular senescence drives HMOX1-dependent evasion of ferroptosis and radioresistance in glioblastoma

Glioblastoma multiforme (GBM) is a persistent challenge in oncology due to its aggressive nature and limited survival. Despite various therapeutic strategies, the recurrence of GBM still exists, driven by the complex cellular diversity and evolutionary dynamics during the treatment process. This study established a radioresistant GBM cell model through repeated exposure to ionizing radiation and revealed a distinct manifestation of cellular senescence of these cells. The comprehensive genomic and transcriptomic analyses identified that IFI16, as a critical driver of cellular senescence, contributed to the radioresistance of GBM. Mechanistically, IFI16 was involved in orchestrating HMOX1 transcription thereby attenuating ferroptosis after irradiation. HMOX1 limited lipid peroxidation, reactive oxygen species (ROS) production, and intracellular Fe2+ content following irradiation, thus effectively counteracting ferroptosis in GBM. Furthermore, IFI16 interacted with the transcription factors JUND and SP1 through its pyrin domain, robustly facilitating HMOX1 expression, further inhibiting ferroptosis and enhancing radioresistance in GBM cells. Notably, glyburide, an anti-aging agent, effectively disrupted IFI16 function and thus enhanced ferroptosis and radiosensitivity. By specifically targeting the pyrin domain of IFI16, glyburide emerged as a potential therapeutic agent against GBM radioresistance. In conclusion, these novel findings underscored the central role of IFI16 in GBM radioresistance and offered promising avenues for innovative therapeutic interventions against GBM radiosensitivity To investigate the function of the IFI16 gene in radioresistance in GBM cells, we established U251MG radioresistant cell lines in which IFI16 was knocked down by shRNA.