Colchicine Directly Targets Aldehyde Dehydrogenase 2 (ALDH2) to Suppress Radiation-Induced Senescence and Atherosclerosis

Background: Ionizing radiation (IR) accelerates atherosclerosis through induction of cellular senescence, DNA damage, defective efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers. Although low-dose colchicine reduces ischemic cardiovascular events in coronary artery disease, the precise molecular mechanisms underlying its vasculoprotective effects remain incompletely defined, and whether it mitigates radiation-associated vascular injury is unknown. Methods: Bone marrow-derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. Molecular effects were assessed by RNA-seq, immunoblotting, and molecular docking. In vivo effects were tested in a partial carotid ligation (PLCL) model using spatial proteomics. Human monocyte-derived macrophages (HMDMs) from thoracic malignancy patients were analyzed before and after radiation therapy (RT). Results: Low-dose colchicine suppressed IR-induced macrophage senescence signaling while preserving NRF2 activity. In a cell-free assay, colchicine directly activated aldehyde dehydrogenase 2 (ALDH2) in a dose-dependent manner (EC50 1-5 nM), identifying ALDH2 as a direct molecular target of colchicine. Following irradiation, colchicine restored ALDH2, reduced mitochondrial (mt)ROS-dependent p90 ribosomal S6 kinase (p90RSK) activation and lipid peroxidation, preserved TET2 and DNMT3A expression, and rescued impaired efferocytosis while preventing nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) depletion. These protective effects were ALDH2-dependent, as they were lost with ALDH2 inhibition or depletion and were mimicked by pharmacologic ALDH2 activation. In vivo, colchicine attenuated radiation-induced atherosclerosis and macrophage senescence-associated stemness (SAS). Consistently, macrophages from patients after RT showed reduced ALDH2 with increased mtROS, lipid peroxidation, and senescence. Conclusion: These findings identify ALDH2 as a previously unrecognized molecular target of colchicine that links mitochondrial redox control to suppression of radiation-induced macrophage senescence and atherosclerosis and may contribute to the efficacy of low-dose colchicine in cardiovascular disease.