IRF4 Enhances Radiosensitivity of Cervical Cancer by Inhibiting the PI3K/Akt/mTOR Pathway to Regulate Autophagy

ABSTRACT Interferon regulatory factor 4 (IRF4), a critical member of the IRF transcription factor family, harbors an elusive biological role in cervical cancer. Through immunohistochemical staining and immunoblotting, CCK‐8 viability assays, EdU incorporation tests, clonogenic survival experiments, flow cytometric detection, transmission electron microscopy, immunofluorescence staining and heterotopic transplantation model, we discover that IRF4 expression was markedly decreased in cervical cancer tissues and cell lines compared to normal controls. Overexpression of IRF4 suppressed proliferation, migration, and invasion in both Siha and HeLa cells, while concurrently enhancing radiosensitivity. Mechanistically, IRF4 upregulated autophagy‐related proteins (LC3, Beclin‐1) and promoted autophagosome formation, while downregulating P62 by inhibiting the PI3K/Akt/mTOR pathway. In vivo studies demonstrated that IRF4 augmented the tumor response to radiation and further potentiated the effects when combined with rapamycin treatment, confirming its pivotal role in promoting radiosensitivity through PI3K/Akt/mTOR‐mediated autophagy. IRF4 emerges as a critical regulator of cervical cancer progression via modulation of autophagy and influences the tumor's response to radiotherapy. It holds promise as a potential therapeutic target to enhance cervical cancer radiosensitivity.