PAICS (phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase) is a bifunctional enzyme catalyzing two sequential reactions in de novo purine biosynthesis, converting aminoimidazole ribonucleotide (AIR) to carboxyaminoimidazole ribonucleotide (CAIR) and subsequently CAIR to N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR) 1. PAICS functions as a critical metabolic hub regulating cellular purine pools. The enzyme undergoes K6-polyubiquitination by the Cul5/ASB11 ubiquitin ligase complex, recruiting UBAP2 to trigger phase separation and purinosome assembly—metabolic compartments that enhance de novo purine synthesis efficiency during cellular stress 2. Post-translational acetylation of PAICS by ACSS2 promotes its autophagy-mediated degradation, limiting purine metabolism and dNTP pools 3. Clinically, PAICS is aberrantly overexpressed in multiple cancers including prostate cancer, melanoma, and non-small cell lung cancer, where it promotes proliferation, invasion, and poor prognosis 415. PAICS activation of the PI3K-Akt-β-catenin pathway drives cancer cell migration 5. Beyond malignancy, reduced PAICS expression in C9orf72-associated amyotrophic lateral sclerosis causes cerebellar neuronal loss and DNA damage accumulation 6. These findings establish PAICS as a potential therapeutic target for cancer and neurodegenerative diseases.