ASXL1 (ASXL transcriptional regulator 1) is an epigenetic regulator that functions as a non-catalytic component of the PR-DUB complex, which specifically deubiquitinates histone H2A monoubiquitinated at lysine 119 (H2AK119ub1), thereby regulating Polycomb-mediated gene silencing 1. The protein acts as a transcriptional coactivator and corepressor in a context-dependent manner, modulating nuclear hormone receptor signaling pathways and controlling genes involved in development, cell communication, and proliferation 2. ASXL1 also has a non-epigenetic cytoplasmic function, suppressing innate immune signaling by inhibiting IRAK1-TAK1 interaction and preventing NF-κB activation 3. Mutations in ASXL1, predominantly frameshift or nonsense mutations generating C-terminally truncated proteins, are frequently observed in clonal hematopoiesis of indeterminate potential (CHIP), affecting 10% of people over 65 years 45. These mutations are associated with increased cardiovascular disease risk, with large ASXL1 CHIP conferring a 45% increased risk of atrial fibrillation and promoting atherosclerosis through dysregulated innate immunity 63. ASXL1 mutations also increase risk for hematologic malignancies and are linked to poor overall survival in cancer patients 72.