Accessible raw data for 'Two Birds with One Stone: Targeting METTL3 Ameliorates Doxorubicin-Induced Endothelial Premature Senescence and Atherosclerosis While Potentiating Its Antitumor Efficacy'

Emerging evidence suggests that cancer survivors who have undergone anthracycline therapy frequently experience late-onset atherosclerosis. However, the mechanisms underlying this phenomenon and potential preventive strategies remain largely unexplored. In this study, we developed a mouse model to replicate doxorubicin (Dox)-induced atherosclerotic lesions. Given the established role of the RNA methylase METTL3 in both atherogenesis and tumorigenesis, we conducted a comprehensive investigation to assess whether targeting METTL3 could mitigate Dox-induced atherosclerosis and enhance the efficacy of Dox in inhibiting tumor progression. Our findings reveal that Dox administration promotes vascular endothelial premature senescence and atherosclerosis, to a large extent by upregulating the expression of METTL3 and its substrate genes, particularly those encoding senescence-associated secreted proteins. To translate METTL3 as a therapeutic target, we developed and characterized an endothelium-targeted (achieved by coating with CD31 antibodies) nanoparticle loaded with the METTL3 inhibitor STM2457 (endothelium-targeted METTL3 nano-inhibitor, ETMN). As anticipated, ETMN effectively protects murine blood vessels against Dox-aggravated endothelial senescence and inflammation, as well as atheroma formation. Furthermore, ETMN, with enhanced enrichment in tumor allografts, significantly potentiates Dox's tumoricidal activity by attenuating METTL3 oncogenic signaling. In summary, our work offers a practical solution for addressing Dox therapy-related atherosclerosis, providing dual benefits and advancing the treatment and management of cancer patients undergoing anthracycline therapy.