Citations 1
Colchicine Directly Targets Aldehyde Dehydrogenase 2 (ALDH2) to Suppress Radiation-Induced Senescence and Atherosclerosis
Abe, Jun‐ichi , Samanthapudi, Venkata Subrahman K, Chen, Weiqing , Tra, Ngoc Tuyet , Mejia, Gilbert F. , Hoang, Oanh, Rivera, Luis Antonio, Chu, Kun Yuan, Osawa, Masaki, Kim, J, Ko, Kyung Ae , Reddy, Anilkumar K. , Moreno, Silvia Fernanda López, Lenz, S., Mendoza, Keila Carolina Ostos , Sanchez, Edgardo, Herrmann, Joerg , Schadler, Keri , Manisty, Charlotte, Yusuf, Syed Wamique , Pathania, Rajneesh , Nead, Kevin T. , Hildebrandt, Michelle, Fuller, C David, Lin, Steve H., Le, Nhat‐Tu , Manisty, Charlotte , Hoang, O.N. , Kim, Jung Hyun , Hoang, Oanh , Abe, Jun-Ichi , Chen, Weiqing , Rivera, Luis Antonio , Kim, Jung Hyun , Lee, Jonghae , Li, Shengyu , Lenz, Stefania Assunto , Herrmann, Joerg , Schadler, Keri , Yvan-Charvet, Laurent , Ameri, Pietro , Yusuf, Syed Wamique , Burks, Jared K , Palaskas, Nicolas L , Fuller, Clifton D. , Koutroumpakis, Efstratios , Krishnan, Sunil , Wang, Guangyu , Kotla, Sivareddy
No container title available | May 30, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract 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 (EC 50 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.