Qiao Shunsong, Tang Chao, Zhu Jingjing, Feng Yu, Xiang Li, Zhu Jing, Gu Xiaosong
Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
FASEB J. 2025 Jun 15;39(11):e70666. doi: 10.1096/fj.202403143RRRR.
While thoracic radiotherapy represents a mainstay therapeutic modality for malignancies, its cardiotoxic sequelae, particularly radiation-induced cardiac fibrosis (RICF), significantly limit clinical outcomes. Emerging evidence implicates the N6-methyladenosine (m6A) methyltransferase METTL3 in pathological cardiac remodeling, though its mechanistic involvement in radiation-associated fibrogenesis remains enigmatic. This investigation elucidates the epigenetic regulation of METTL3 in RICF pathogenesis. X-ray-modulated RICF mice models were constructed to investigate the role of METTL3 in cardiac fibroblasts. Simultaneously, METTL3 overexpression and silencing were conducted on fibroblasts and mice hearts to evaluate pro-fibrotic protein expression, cardiac fibrosis, and heart function. Radiation impairs cardiac function and induces myocardial fibrosis. Elevated METTL3 expression was observed in irradiated mouse hearts and cardiac fibroblasts. During irradiation, METTL3 promoted fibroblast proliferation and differentiation into myofibroblasts. Overexpression of METTL3 in cardiac fibroblasts was associated with increased expression of pro-fibrotic proteins and intensified fibrosis, and silencing of METTL3 attenuated these adverse effects. Mechanistically, METTL3 promotes m6A modification of Akt mRNA and enhances its stability by recognizing the m6A-reading protein IGF2BP1, which activates the Akt/mTOR signaling pathway to promote fibroblast proliferation and differentiation toward myofibroblasts, thereby inducing cardiac fibrosis. Furthermore, pharmacological administration of STM2457, a highly selective METTL3 inhibitor, effectively ameliorated cardiac fibrosis in mice. Our findings establish METTL3 as a novel epigenetic regulator of RICF through m6A-Akt/mTOR axis activation. The demonstrated efficacy of METTL3-targeted intervention provides mechanistic justification for developing precision cardioprotective strategies during radiotherapy. This work advances our understanding of epitranscriptomic control in radiation-associated cardiotoxicity and highlights the translational potential of m6A-targeted therapies.
虽然胸部放疗是恶性肿瘤的主要治疗方式，但其心脏毒性后遗症，尤其是放射性心脏纤维化（RICF），严重限制了临床疗效。新出现的证据表明，N6-甲基腺苷（m6A）甲基转移酶METTL3参与病理性心脏重塑，但其在辐射相关纤维化形成中的机制仍不清楚。本研究阐明了METTL3在RICF发病机制中的表观遗传调控作用。构建X射线诱导的RICF小鼠模型，以研究METTL3在心脏成纤维细胞中的作用。同时，在成纤维细胞和小鼠心脏中进行METTL3过表达和沉默实验，以评估促纤维化蛋白表达、心脏纤维化和心脏功能。辐射会损害心脏功能并诱导心肌纤维化。在受照射的小鼠心脏和心脏成纤维细胞中观察到METTL3表达升高。在照射期间，METTL3促进成纤维细胞增殖并分化为肌成纤维细胞。心脏成纤维细胞中METTL3的过表达与促纤维化蛋白表达增加和纤维化加剧相关，而METTL3的沉默则减弱了这些不良反应。机制上，METTL3促进Akt mRNA的m6A修饰，并通过识别m6A阅读蛋白IGF2BP1增强其稳定性，从而激活Akt/mTOR信号通路，促进成纤维细胞增殖并向肌成纤维细胞分化，进而诱导心脏纤维化。此外，高选择性METTL3抑制剂STM2457的药物给药有效改善了小鼠的心脏纤维化。我们的研究结果表明，METTL3通过激活m6A-Akt/mTOR轴，是RICF的一种新型表观遗传调节因子。METTL3靶向干预的疗效为放疗期间制定精准心脏保护策略提供了机制依据。这项工作增进了我们对辐射相关心脏毒性中表观转录组控制的理解，并突出了m6A靶向治疗的转化潜力。
