Heptachlor Epoxide Enhances Ovarian Cancer Invasion by NF‐κB Activation Mediated MMP‐2/‐9 Expression

Environmental pollutants, particularly persistent organochlorine pesticides with endocrine-disrupting effects, are increasingly raising concerns about the potential hazards to women's reproductive health. This study focuses on heptachlor epoxide, one of these pollutants, investigating whether it drives the invasion and metastasis of ovarian cancer, a common malignancy in women, and the underlying mechanisms. In vitro experiments showed that heptachlor epoxide significantly and dose-dependently enhanced the invasive ability of SKOV-3 ovarian cancer cells. Further transcriptomic and molecular biology analyses revealed that this pollutant specifically upregulates the expression of matrix metalloproteinases MMP-2 and MMP-9. Mechanistically, the study found that heptachlor epoxide activates the NF-κB signaling pathway by inducing phosphorylation and degradation of IκBα, driving the nuclear translocation of the p65 subunit; intervention with the NF-κB-specific inhibitor JSH-23 effectively blocked the upregulation of these MMPs and reversed the proinvasive effects. Key in vivo experiments further confirmed that in an orthotopic ovarian cancer transplantation model, exposure to heptachlor epoxide significantly increased the number and burden of intraperitoneal metastases in mice, and this effect also depended on the NF-κB pathway. This study systematically elucidates for the first time the complete molecular pathway by which heptachlor epoxide drives ovarian cancer invasion and metastasis through the NF-κB/MMP axis, providing solid toxicological evidence for assessing the risk of such environmental pollutants in the malignant progression of ovarian cancer.