PARP14 is a mono-ADP-ribosyltransferase that catalyzes the transfer of ADP-ribose units from NAD+ to target proteins, distinct from canonical PARPs in that it mediates only mono-ADP-ribosylation, not poly-ADP-ribosylation. The enzyme contains three macrodomains, a WWE domain, and a catalytic ARTD domain that collectively enable substrate binding and the mono-ADP-ribosylation reaction 1. Beyond transferase activity, PARP14 exhibits hydrolase activity through its macrodomain 1, allowing it to both add and reverse ADP-ribose modifications 2. PARP14 plays a central role in interferon-induced signaling, serving as a major responder to interferon-γ stimulation 3. Upon interferon stimulation, PARP14 catalyzes mono-ADP-ribosylation of signaling proteins including STAT1 and STAT6, thereby modulating immune responses and transcriptional regulation 4. The enzyme localizes to interferon-induced p62 bodies, where ADP-ribosylated substrates accumulate in a process dependent on the ubiquitin-proteasome system 5. Clinically, PARP14 inhibition aggravates stroke outcomes in murine models, with PARP14 overexpression suppressing microglial activation and promoting functional recovery, suggesting a neuroprotective role 6. Given that viral macrodomains from SARS-CoV-2 efficiently reverse PARP14-mediated ADP-ribosylation, this pathway represents a key host–pathogen interface 2. PARP14 inhibitors are being explored as anti-cancer and anti-inflammatory agents, though current evidence does not establish a clear advantage for selective over pan-PARP inhibition 1.