PARP15 is a mono-ADP-ribosyltransferase that catalyzes the transfer of single ADP-ribose moieties from NAD+ to target proteins and RNA 1. The enzyme functions as a transcriptional corepressor and requires dimerization of its catalytic domain for enzymatic activity, with dimerization enabling proper target engagement rather than affecting NAD+ binding 2. PARP15 operates in the cytoplasm and nucleus, mediating protein modifications through its NAD+-dependent transferase activity 3. Clinically, PARP15 represents a critical genetic determinant of vascular barrier function. Loss-of-function mutations in PARP15 are associated with monoclonal gammopathy-associated capillary leak syndrome (MG-CLS), a condition characterized by severe vascular leakage and sepsis-like complications 4. Mechanistically, PARP15 protects vascular endothelial barrier integrity by ADP-ribosylating the scaffold protein JIP3, which suppresses p38 MAP kinase activation and cytokine-induced barrier disruption 4. Mice expressing inactive PARP15(G628R) demonstrate enhanced inflammation-associated vascular leakage in a p38-dependent manner 4. As a therapeutic target, PARP15 is amenable to small-molecule inhibition, with crystal structures demonstrating ligand-binding modes compatible with marketed PARP inhibitors 5. However, selective PARP15 inhibitors remain under development, as most existing compounds lack specificity 3.