Abstract Body: Introduction: Ionizing radiation (IR) promotes cellular senescence, DNA damage, impaired efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers, collectively accelerating radiation-induced atherosclerosis (AthS); however, the mechanisms by which colchicine modulates these processes remain unclear.
Hypothesis: Colchicine attenuates IR-induced inflammation and senescence, including CH-associated pathways, thereby limiting AthS progression.
Methods: Bone marrow-derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. RNA sequencing and Western blot analyses assessed molecular changes. IR-induced senescence was assessed using a CellAge-based composite senescence score together with GSEA and GO pathway enrichment analyses. Structual docking was performed using AutoDock Vina v1.2.5 employing the default vina scoring function. In vivo effects of colchicine on radiation-induced AthS were evaluated using a partial carotid ligation model, with spatial proteomic changes assessed by CO-Detection by Indexing (COMET) analysis.
Results: Colchicine did not broadly suppress IR-induced inflammatory gene expression but robustly restored Aldehyde Dehydrogenase (ALDH)1/2, which was markedly downregulated by IR. While NF-κB activation was only partially reduced, colchicine significantly decreased inflammatory cytokine secretion and suppressed senescence phenotypes, including SA-β-gal activity, mitochondrial reactive oxygen specoes, Nuclear Factor Erythroid 2–Related Factor loss, and NAD/ATP depletion, accompanied by reduced senescence transcriptional signatures. Colchicine did not inhibit early IR-induced p90RSK activation, indicating a downstream mechanism. Pharmacologic ALDH2 activation (Alda-1) recapitulated, whereas ALDH2 inhibition (CVT-10216) abolished, colchicine’s anti-senescent effects. Docking and in tube enzyme assays demonstrated direct, dose-dependent activation of ALDH2 by colchicine. In vivo, colchicine attenuated IR-accelerated AthS and senescence markers. After radiation therapy (RT), human monocyte-derived macrophages showed reduced ALDH2 and accumulation of downstream 4-Hydroxynonenal (4-HNE), indicating impaired aldehyde detoxification and oxidative stress in cancer patients after RT.
Conclusion: Colchicine directly activates ALDH2 to suppress radiation-induced senescence and inflammation, revealing a novel mechanism and therapeutic strategy for radiation-associated cardiovascular disease in cancer patients.