Overexpression of GJB1-13k induces mitochondrial calcium overload and triggers apoptosis and GSDME-mediated pyroptosis in cervical cancer

Cervical Cancer, the fourth most common female malignancy worldwide, is often diagnosed at advanced stages in developing countries, where survival declines dramatically from 91% to about 17%, underscoring the urgent need for new therapies. In this study, we demonstrated that overexpression of GJB1-13k, a truncated isoform of connexin 32 (Cx32) mediated by an internal ribosome entry site (IRES), significantly inhibited cervical Cancer growth both in vitro and in vivo. Mechanistically, we found that GJB1-13k triggers mitochondrial calcium overload, which in turn activates caspase-dependent pathways that induce both Apoptosis and GSDME-mediated Pyroptosis. Additionally, we identified a physical interaction between GJB1-13k and the inositol 1,4,5-trisphosphate receptor type 3 (ITPR3), an endoplasmic reticulum Calcium Channel, which may contribute to the observed calcium dysregulation and cell death. Our findings suggest that overexpressing GJB1-13k may represent a promising new strategy for the treatment of cervical Cancer.