CTDSP1 (CTD small phosphatase 1) is a nuclear phosphatase that preferentially dephosphorylates serine-5 residues within the heptapeptide repeats of RNA polymerase II's C-terminal domain (CTD), thereby negatively regulating transcription during the transition from initiation to elongation 1. CTDSP1 functions as a component of the REST repressor complex, silencing neuronal genes in non-neuronal cells through RE-1 element-mediated mechanisms 1. Beyond transcriptional regulation, CTDSP1 dephosphorylates multiple oncogenic substrates including AKT1, Ras family proteins, TWIST1, c-MYC, and regulates the retinoblastoma protein (pRb) at the G1/S cell-cycle checkpoint 2. CTDSP1 exhibits prominent tumor suppressor activity in clear cell renal cell carcinoma (ccRCC), where CTDSP1 overexpression significantly inhibits cell growth and associates with improved patient survival 3. In lung cancer, CTDSP1 suppresses progression and metastasis via AhR-ARNT signaling and exosomal miR-26b transfer 4. Conversely, CTDSP1 inhibition by rabeprazole promotes irinotecan resistance in colorectal cancer by facilitating topoisomerase I degradation 5. CTDSP1 knockdown promotes peripheral nerve regeneration by destabilizing REST, enhancing neurotrophic factor expression 6. Notably, human CTDSP1 functionally conserves with yeast HAD phosphatases in regulating TORC1-autophagy signaling under amino acid limitation 7. These diverse functions underscore CTDSP1's multifaceted role in transcriptional regulation, cell-cycle control, and therapeutic resistance.