biostudies-literatureHsu CCMinistry of Science and Technology, TaiwanDuke University School of MedicineWake Forest School of MedicineNational Cancer InstituteNCI NIH HHSNational Institutes of HealthAnderson Discovery Professor for Cancer ResearchNIH HHSe20231832https://www.ebi.ac.uk/biostudies/studies/S-EPMC11528126biostudies-literatureUnknown221(11)Acquisition of prostate cancer stem cells (PCSCs) manifested during androgen ablation therapy (ABT) contributes to castration-resistant prostate cancer (CRPC). However, little is known about the specific metabolites critically orchestrating this process. Here, we show that IMPA1-derived inositol enriched in PCSCs is a key metabolite crucially maintaining PCSCs for CRPC progression and ABT resistance. Notably, conditional Impa1 knockout in the prostate abrogates the pool and properties of PCSCs to orchestrate CRPC progression and prolong the survival of TRAMP mice. IMPA1-derived inositol serves as a cofactor that directly binds to and activates IMPDH2, which synthesizes guanylate nucleotides for maintaining PCSCs with ARlow/- features leading to CRPC progression and ABT resistance. IMPA1/inThe Journal of experimental medicineIMPA1-derived inositol maintains stemness in castration-resistant prostate cancer via IMPDH2 activation.PMC11528126R01CA270617R01 CA277682R01 CA256158R01CA248037P30 CA012197105-2917-I-564-067R01 CA270617R01CA277682R01 CA248037R01CA256158P30CA012197Manne RKHuang JChen MWang GLi HYZhou XHsu CCGu HPeng DChen ZZhang XCai ZLin HKLi CFPan BSDeep GPenugurti VWang YArmstrong AJXu ZChen TfalseIMPA1-derived inositol maintains stemness in castration-resistant prostate cancer via IMPDH2 activation.Acquisition of prostate cancer stem cells (PCSCs) manifested during androgen ablation therapy (ABT) contributes to castration-resistant prostate cancer (CRPC). However, little is known about the specific metabolites critically orchestrating this process. Here, we show that IMPA1-derived inositol enriched in PCSCs is a key metabolite crucially maintaining PCSCs for CRPC progression and ABT resistance. Notably, conditional Impa1 knockout in the prostate abrogates the pool and properties of PCSCs to orchestrate CRPC progression and prolong the survival of TRAMP mice. IMPA1-derived inositol serves as a cofactor that directly binds to and activates IMPDH2, which synthesizes guanylate nucleotides for maintaining PCSCs with ARlow/- features leading to CRPC progression and ABT resistance. IMPA1/in2024-01-01T00:00:00Z2024 Nov2026-06-01T07:50:09.753Z2025-07-03T03:04:55.411ZS-EPMC115281263947068910.1084/jem.20231832