NUDT16 is a nudix hydrolase with dual catalytic functions as both an RNA decapping enzyme and a nucleotide phosphatase. As an RNA-binding protein, it catalyzes metal-dependent cleavage of 7-methylguanosine (m7G) cap structures on U8 snoRNA, mRNAs, and other RNA species, leaving 5'-monophosphate products 1. Its decapping activity extends to NAD- and FAD-capped RNAs, with preference for substrates containing guanine in the first transcribed nucleotide 1. As a phosphatase, NUDT16 removes non-canonical purine nucleotides (inosine diphosphate, deoxyinosine diphosphate, and xanthine diphosphate) from cellular nucleotide pools, preventing their incorporation into RNA and DNA 2. NUDT16 functions as a dimer with substrate specificity determined by purine ring substituents and product-release rate regulation 2. Beyond classical decapping roles, NUDT16 regulates DNA homologous recombination repair through ADP-ribosyl hydrolysis (dePARylation) of CtIP and HMGA1 proteins, controlling their stability and recruitment to double-strand breaks 34. Additionally, NUDT16-mediated dePARylation of DNMT1 regulates replication fork stability and DNA repair efficiency 5. These functions collectively position NUDT16 as a critical regulator of RNA metabolism and DNA damage responses. NUDT16 is downregulated in idiopathic pulmonary fibrosis and implicated in sepsis pathogenesis 67.