RBBP9 is a serine hydrolase that functions as an RB-binding protein regulating multiple cellular processes. Structurally, RBBP9 contains an α/β hydrolase fold with a catalytic triad (Ser75-His165-Asp138) 1. Primary functions include: (1) cell cycle regulation through RB/E2F pathway interaction 2, (2) prodrug activation—RBBP9 catalyzes hydrolytic conversion of valacyclovir to active acyclovir with catalytic efficiency comparable to known VACV-activating enzymes 3, and (3) negative regulation of TGF-β and JAK/STAT1 signaling by suppressing SMAD2/3 and STAT1 phosphorylation 14. Disease relevance is substantial. RBBP9 is tumor-associated and required for pancreatic carcinoma development 1; reduced RBBP9 expression increases susceptibility to colitis and colitis-associated cancer through enhanced JAK/STAT1 activation 4. Conversely, RBBP9 represents a synthetic-lethal vulnerability in Fanconi anemia-deficient head-and-neck squamous cell carcinomas, where the FDA-approved inhibitor emetine selectively kills FA-HNSCC cells 5. Clinically, RBBP9 inhibition decouples hPSC proliferation from differentiation without affecting pluripotency 2, while RBBP9-targeting drugs show therapeutic promise in specific cancer contexts requiring further clinical development.