SPC25 is a structural component of the NDC80 kinetochore complex essential for chromosome 2 and spindle checkpoint function. It organizes stable microtubule-binding sites in the outer kinetochore and synergistically enhances the affinity of the SKA1 complex for microtubules, allowing tracking of depolymerizing microtubules. Beyond its canonical kinetochore role, SPC25 is upregulated across multiple malignancies and drives oncogenic pathways. In epithelial ovarian cancer, SPC25 scaffolds an RIOK1/MYH9 complex that promotes nuclear MYH9 accumulation and Wnt/β-catenin signaling, sustaining cancer stem cell phenotypes and platinum resistance 1. In breast cancer, elevated SPC25 associates with poor recurrence-free, metastasis-free, and overall survival and promotes cell cycle progression and DNA damage responses 2. In lung adenocarcinoma, SPC25 upregulation correlates with advanced staging, activates glycolytic pathways and cell cycle checkpoints, and enhances immune escape through glutamine metabolism 34. Similar overexpression and adverse prognostic associations occur in hepatocellular carcinoma and non-small cell lung cancer 56. In lung cancer with idiopathic pulmonary fibrosis, SPC25 mutations occur in 53% of cases and are associated with transforming growth factor-β1-mediated epithelial-to-mesenchymal transition; paclitaxel and DNMT1 inhibitors suppress SPC25 expression 7. In non-small cell lung cancer, berberine inhibits tumor growth by targeting the SPC25/NUF2 axis 6, offering a potential therapeutic approach.