PIDD1 (p53-induced death domain protein 1) is a multifunctional death domain protein that serves as a critical hub in DNA damage response and cellular stress pathways. Functionally, PIDD1 operates primarily through assembly of the PIDDosome, a multiprotein complex containing RAIDD and caspase-2, which promotes apoptosis in response to unresolved DNA interstrand crosslinks 1. This assembly is precisely controlled by stepwise phosphorylation and SUMOylation events at conserved residues 1. Beyond apoptosis, PIDD1 engages multiple signaling pathways: it associates with IKBKG and RIPK1 to enhance NF-κB activation 2, and regulates caspase-2-mediated cell death in response to centrosome aberrations 3. PIDD1 displays intein-like features enabling production of distinct polypeptides from a single precursor, facilitating diverse biological functions including cell cycle control and sterile inflammation 4. Clinically, biallelic PIDD1 mutations cause autosomal recessive intellectual developmental disorder with neuropsychiatric features and lissencephaly, characterized by cortical thickening and mTOR pathway dysregulation 5. Genome-wide association studies identify PIDD1 as a putatively causal gene for ADHD in fetal cortical tissues 6. PIDD1 is downregulated in lung adenocarcinoma through p53 ubiquitination by the E3 ligase DCAF13, suggesting its loss promotes cancer progression 7.