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.

越来越多的证据显示，接受蒽环类疗法的癌症幸存者常出现迟发性动脉粥样硬化。然而，该现象背后的潜在机制与潜在预防策略仍未得到充分探索。本研究构建了小鼠模型以模拟多柔比星（Dox）诱导的动脉粥样硬化病变。鉴于RNA甲基化酶METTL3在动脉粥样硬化发生与肿瘤发生中的既定作用，我们开展了全面研究，以评估靶向METTL3是否可缓解Dox诱导的动脉粥样硬化，并增强Dox抑制肿瘤进展的疗效。本研究结果表明，Dox给药可通过上调METTL3及其底物基因的表达（尤其是编码衰老相关分泌蛋白的基因），在很大程度上促进血管内皮细胞早衰与动脉粥样硬化的发生。为将METTL3开发为治疗靶点，我们设计并表征了一种内皮靶向纳米颗粒：通过包被CD31抗体实现内皮靶向，负载METTL3抑制剂STM2457，即内皮靶向METTL3纳米抑制剂（ETMN）。正如预期，ETMN可有效保护小鼠血管免受Dox加重的内皮衰老与炎症反应，同时抑制动脉粥样斑块形成。此外，ETMN在肿瘤异体移植组织中富集度更高，可通过抑制METTL3致癌信号通路，显著增强Dox的抗肿瘤活性。综上，本研究为解决Dox治疗相关动脉粥样硬化提供了切实可行的方案，兼具双重获益，有望改善接受蒽环类疗法的癌症患者的诊疗与管理。