CTDSPL2 (CTD small phosphatase like 2) is a nuclear serine/threonine phosphatase with multiple cellular functions. Its primary function involves promoting gluconeogenesis by dephosphorylating FOXO1 and FOXO3A transcription factors, leading to their nuclear retention and enhanced transcriptional activity on key gluconeogenic enzymes PEPCK1 and G6PC 1. The protein also functions as a chr15-associated CTD phosphatase with preferential activity against Ser5 phosphorylation of RNA polymerase II, localizing particularly to transcriptionally silenced chr15 regions 2. CTDSPL2 plays important roles in cellular processes including epithelial-to-mesenchymal transition through Snail dephosphorylation and stabilization 3, and cell cycle regulation through mitotic phosphorylation by CDK1 4. In erythroid differentiation, CTDSPL2 can enhance expression of ε- and γ-globin genes, suggesting potential therapeutic applications for sickle cell disease and β-thalassemia 5. The protein undergoes dynamic subcellular translocation during erythroid differentiation, gradually releasing from chr15 to accumulate in the cytoplasm 2. Disease relevance includes associations with necrotizing enterocolitis through DNA hypermethylation 6 and potential roles in pancreatic cancer progression 4.