Pseudoginsenoside F11 enhances YBX1-mediated transcriptional repression of PRPS2 to inhibit the stemness and pulmonary metastasis of triple negative breast cancer

Background: Hyperactive de novo nucleotide synthesis is a metabolic hallmark of pulmonary metastatic triple-negative breast cancer (TNBC), largely driven by the upregulation of phosphoribosyl pyrophosphate synthetase 2 (PRPS2). The absence of specific PRPS2 inhibitors represents a significant unmet therapeutic need for preventing TNBC metastasis. Methods: We screened a library of 320 traditional Chinese herb-derived compounds using a PRPS2-promoter-driven luciferase reporter assay in TNBC cells. The lead compound was evaluated in vitro for effects on PRPS2 expression and cancer stemness, and in vivo using a murine pulmonary metastasis model. The direct target of PF11 was identified via biotin-conjugated pull-down assays. Mechanistic insights were gained through chromatin immunoprecipitation (ChIP) and reporter assays. Results: Pseudoginsenoside F11 (PF11) was identified as a potent inhibitor of PRPS2 transcription. Treatment with PF11 significantly suppressed PRPS2 expression, cancer cell stemness, and pulmonary metastasis in murine models. We identified the transcription factor YBX1 as the direct binding target of PF11. PF11 binding enhanced YBX1's affinity with the PRPS2 promoter, enabling it to compete with and displace the transcriptional activator c-Myc. Subsequently, YBX1 recruited the NuRD corepressor complex to the promoter, leading to transcriptional repression of PRPS2. Conclusion: Our findings unveil a novel mechanism by which PF11 activates a YBX1-NuRD corepressor complex to downregulate PRPS2, thereby attenuating TNBC stemness and metastasis. We propose PRPS2 as a druggable target and PF11 as a promising natural compound for the targeted therapy of TNBC.