SEPTIN6 is a filament-forming cytoskeletal GTPase that functions as a key component of the septin complex, a fourth cytoskeletal system distinct from actin, microtubule, and intermediate filaments. Mechanistically, SEPTIN6 forms dynamic multivalent interactions through its C-terminal tail that undergo liquid-liquid phase separation (LLPS), enabling assembly of higher-order septin structures essential for cytoskeletal organization 1. The protein is critical for establishing epithelial cell polarity and adherens junction integrity 1, and participates in cytokinesis and actin cytoskeleton organization. SEPTIN6 also functions in endosomal protein sorting during multivesicular body (MVB) biogenesis by regulating AP-3 and ESCRT machinery interactions 2, and contributes to podosome maturation and endothelial cell invasion during angiogenesis 3. Clinically, SEPTIN6 is implicated in pediatric acute myeloid leukemia (AML) through recurrent MLL-SEPTIN6 fusion translocations, particularly in infant cases with complex chrX abnormalities involving 11q23 and Xq24 456. Additionally, SEPTIN6 was identified as an upregulated feature gene associated with atrial fibrillation in patients with valvular heart disease 7, suggesting broader cardiovascular relevance.