PARP4 is a mono-ADP-ribosyltransferase primarily localized to the cytoplasmic vault organelle, a massive ribonucleoprotein complex 1. Its N-terminal region contains a BRCT domain homologous to PARP1 that mediates nucleic acid binding, particularly to vault-associated noncoding RNA 2. Structurally, PARP4 integrates into the major vault protein (MVP) cage where it accesses NAD+ binding pockets, suggesting its enzymatic activity is substrate-proximal within the vault 1. Beyond its canonical vault function, PARP4 operates as a tumor suppressor in lung adenocarcinoma through interaction with the splicing regulator hnRNPM, independent of the vault complex 3. Loss or mutation of PARP4 promotes KRAS- or EGFR-driven tumorigenicity via dysregulated intronic splicing 3. Clinically, PARP4 mutations show mutual exclusivity with NFE2L2/KEAP1 alterations in squamous cell lung cancer, suggesting distinct pathway roles in oxidative stress response 4. Germline PARP4 variants associate with increased thyroid cancer susceptibility, with pseudogene PARP4P2 variants potentially conferring multiple primary cancer risk 5. Additionally, PARP4 genetic polymorphisms modify susceptibility to particulate matter and bisphenol A exposure-related metabolic and hepatic dysfunction 67.