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Cervical cancer remains a significant global health challenge, particularly in developing countries where access to HPV vaccination is limited. We previously demonstrated that caerin 1.1/1.9 (F1F3) peptides inhibit tumour growth in vitro and in vivo by inducing pyroptosis, followed by apoptosis and immune activation. In this study, we elucidate the molecular mechanisms underlying F1F3-induced pyroptosis in HeLa cells. Our results show that F1F3 triggers pyroptosis independently of GSDME, as evidenced by comparable IL-18 and LDH release in both wild type and GSDME knockout cells. Cross-linking mass spectrometry identified the interaction of F1 to KHDRBS1 and F3 to DDX5, respectively. Knockout of either KHDRBS1 or DDX5 enhanced HeLa cell sensitivity to F1F3 and significantly elevated IL-18 secretion. Notably, KHDRBS1-deficint tumours displayed accelerated growth yet responded more robustly to F1F3 treatment, suggesting a context-dependent tumour-suppressive role of KHDRBS1. These findings uncover a previously uncharacterised pathway regulated by KHDRBS1-DDX5 and demonstrate that F1F3 can effectively interfere with this axis to induce anti-tumour immune responses, highlighting their potential as novel therapeutic agents for cervical cancer.
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