SEPTIN4 is a GTPase-binding septin protein that functions as a pro-apoptotic regulator through multiple interconnected mechanisms. Structurally, SEPTIN4 encodes an alternative splice variant called ARTS (Apoptosis-related protein in TGF-β signaling), which localizes to mitochondria 1. SEPTIN4 promotes apoptosis primarily by binding and inhibiting XIAP, reducing XIAP protein levels and enabling caspase activation 2. Additionally, SEPTIN4 mediates BCL2-XIAP interactions, facilitating proteasomal degradation of both BCL2 and XIAP 1. As a p53 target gene, SEPTIN4/ARTS enhances mitochondrial apoptosis by promoting p53 mitochondrial localization and its interaction with BCL-XL 1. Post-translational regulation occurs through acetylation at K174, where SIRT2-mediated deacetylation inhibits the PARP1-caspase3 apoptotic pathway 3, while WWP2-catalyzed ubiquitination of K174 promotes SEPTIN4 degradation and endothelial protection 4. SEPTIN4 dysfunction associates with spermatogenic failure and reduced expression correlates with poor prognosis in colorectal cancer 2. In hypertensive nephropathy and atherosclerosis, SEPTIN4 dysregulation contributes to pathological remodeling, representing potential therapeutic targets for cardiovascular and renal diseases 3, 5.