Inhibition of XPOT promotes breast cancer cell pyroptosis to suppress cancer progression.

Introduction: Breast cancer (BC) remains a significant threat to women's health, necessitating the identification of new targets to inhibit its progression. Pyroptosis, a form of programmed cell death characterized by cellular swelling, distortion, and increased inflammatory factors, has emerged as a potential mechanism. High expression of exportin-T (XPOT) is linked to poor prognosis in BC patients, but its role in BC progression is not well understood. Material and methods: We used the GEPIA database to analyze XPOT expression in BC and confirmed XPOT levels in BC tissues via immunohistochemistry. Western blotting was used to assess XPOT expression in various BC cell lines. We transfected small interfering RNAs (siRNAs) targeting XPOT and verified the transfection efficiency using Western blotting. The impact of si-XPOT on MCF-7 cell proliferation and apoptosis was measured using CCK-8 and TdT-mediated dUTP nick-end labeling assays. Scratch and Transwell assays were used to evaluate cell metastasis. Enzyme-linked immunosorbent assay was used to measure pyroptosis-associated inflammatory factors interleukin (IL)-1β and IL-18. Western blotting was used to detect pyroptosis-related proteins gasdermin D (GSDMD) and inflammasome components. Results: XPOT expression was elevated in BC tissues, with higher levels in MCF-7 cells compared to other BC cells. Silencing XPOT reduced MCF-7 cell viability, migration, and invasion. Inhibition of XPOT increased pyroptosis-associated inflammatory factors, elevated N-terminal shear levels of GSDMD, and upregulated NLRP3, ASC, and cleaved-caspase1 expression. The pyroptosis inhibitor azalamellarin N reversed the effects induced by si-XPOT. Conclusions: Silencing XPOT promotes pyroptosis in BC cells and inhibits BC progression, suggesting that targeting XPOT could offer new therapeutic avenues for BC treatment.