Single-Cell and Integrative Analyses Uncover Therapeutic Potential of RFX1-Mediated Cuproptosis in PitNETs.

Pituitary neuroendocrine tumors (PitNETs) have different cell types and levels of growth. We do not fully understand why they grow so much. Cuproptosis is a new way that copper kills cells and it is important in cancer. But, we do not know how it works in PitNETs yet. We used several methods like bulk and single-cell sequencing with machine learning to investigate cuproptosis in PitNETs. We used Weighted Gene Co-expression Network Analysis (WGCNA) and random forest to find important genes. Then, we did tests in the lab to see how these genes work. Analysis of cuproptosis-related genes (CRGs) revealed significant differences in expression and immune landscapes between invasive and non-invasive PitNETs. We established CRG-based molecular subtypes and a high-performance predictive model for tumor invasiveness. Notably, regulatory factor X1 (RFX1) was identified and validated as a key regulator that suppresses tumor growth and sensitizes cells to cuproptosis. These results highlight the clinical relevance of cuproptosis in PitNET progression and suggest RFX1 as a potential therapeutic target. This study establishes a single-cell-based molecular landscape of PitNETs and uncovers RFX1-mediated cuproptosis as a key suppressive mechanism of tumor progression. These findings not only deepen the understanding of PitNET heterogeneity but also propose RFX1 as a promising therapeutic target for PitNETs.