Integrating single-cell and bulk RNA sequencing data reveals RGS4 as a functional driver in a proliferative subgroup of SF-1 lineage PitNETs

Introduction: The molecular determinants underlying the heterogeneity and proliferative behavior of Steroidogenic Factor-1 (SF-1) lineage Pituitary Neuroendocrine Tumors (PitNETs) remain insufficiently defined. Methods: We performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic datasets from SF-1 lineage PitNETs to identify molecular subgroups and their defining biomarkers. The functional significance of the top candidate gene, Regulator of G-protein Signaling 4 (RGS4), was examined using gain- and loss-of-function approaches and pharmacological inhibition in pituitary adenoma cell lines. Mechanistic studies were conducted using protein interaction and stability assays. Results: enhances tumor cell proliferation and inhibits apoptosis. Mechanistically, RGS4 promotes p53 ubiquitination, resulting in its destabilization and proteasomal degradation. Conclusion: expression. RGS4 promotes tumor proliferation by destabilizing p53, highlighting the RGS4-p53 axis as a promising therapeutic target.