Exogenous kisspeptin-10 treatment shows pleiotropy via induction of KISS1 expression, metastasis suppression, and promotes apoptosis in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 receptors making it highly clinically challenging subtype pf breast cancer. In this study, we investigated the effect of exogenous Kisspeptin-10 (Kp-10), on MDA-MB-231 and MDA-MB-468 cells. TNBC cells using both in vitro and in silico approaches. Kp-10 treatment significantly reduced cell viability and migration and induced a dose-dependent upregulation of KISS1 mRNA, suggesting a positive feedback loop. Alongside this, Kp-10 modulated key transcription factors-upregulating GATA2, CDX2, and FLI1 while downregulating ZEB1-indicating a shift towards a less aggressive transcriptional state. EMT reversal was evident from increased E-cadherin and β-catenin, and reduced N-cadherin, CD44, and Vimentin. Pro-apoptotic genes CASP3, CASP8, CASP9, and BAX were upregulated, while BCL2 was suppressed, suggesting activation of both apoptotic pathways. Metabolomics profile unveiled the changes in pathways related to apoptosis, anti-angiogenesis, and redox homeostasis. In silico analyses confirmed reduced KISS1 expression in metastatic TNBC tissues and highlighted a correlation between high GATA2/CASP9 levels and improved survival. Kisspeptin-10 reactivates KISS1 and induces anti-tumor effects via transcriptional, apoptotic, and metabolic reprogramming, highlighting its potential as a therapeutic agent in triple-negative breast cancer.