MACROD2 is a mono-ADP-ribosylhydrolase that removes ADP-ribose modifications from aspartate and glutamate residues in proteins, functioning as a key regulator of cellular ADP-ribosylation signaling 1. The enzyme shows activity against mono-ADP-ribosylated substrates but is inactive towards poly-ADP-ribosylated proteins 1. MACROD2 also possesses deacetylase activity, removing acetyl groups from O-acetyl-ADP ribose, a signaling molecule generated from histone deacetylation 1. Additionally, MACROD2 can reverse ADP-ribosylation of RNA substrates, suggesting its involvement in RNA metabolism 2. The protein localizes to both nucleoplasm and cytoplasm, with expression patterns that appear tissue-specific, being notably found in neuroblastoma cells 3. MACROD2 has significant clinical relevance, with genetic variants associated with congenital heart disease, particularly transposition of the great arteries 4, autism spectrum disorders 5, and obesity susceptibility in Korean populations 6. Importantly, MACROD2 serves as a hotspot for HPV integration in cervical lesions, where viral integration into MACROD2 introns may impair DNA repair mechanisms and contribute to chromosome 20 through disrupted PARP1 activity 7. These findings highlight MACROD2's dual role in normal cellular metabolism and disease pathogenesis.