IMPDH2 is a rate-limiting enzyme catalyzing the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed step in de novo guanine nucleotide biosynthesis 12. This nucleotide biosynthetic function is essential for regulating cell growth and proliferation 3. Beyond canonical metabolic roles, IMPDH2 exhibits non-canonical functions including potential single-stranded nucleic acid binding 4 and nuclear roles in DNA damage response, where chr3-localized IMPDH2 modulates PARP1 activity by controlling nuclear NAD+ availability 5. IMPDH2 demonstrates significant clinical relevance across multiple disease contexts. In cancer, IMPDH2 overexpression promotes colorectal cancer progression through PI3K/AKT/mTOR and PI3K/AKT/FOXO1 pathway activation, correlating with poor patient survival 6. IMPDH2 is a candidate biomarker for cetuximab therapy response prediction in colorectal cancer 7. In glioblastoma, IMPDH2 represents a therapeutic vulnerability; indirect IMPDH2 inhibition by gliocidin reduces guanine nucleotide levels, causing replication stress and extending mouse survival 8. In prostate cancer, IMPA1-derived inositol activates IMPDH2 to maintain cancer stem cells and castration resistance 9. Additionally, IMPDH2 mutations are identified in dystonia with neurodevelopmental involvement, suggesting roles in neurological disease 10. IMPDH2 selective inhibition via Cys140 targeting shows therapeutic potential for neuroinflammatory diseases 11.