METTL3 Modulates Radiation-Induced Cardiac Fibrosis via the Akt/mTOR Pathway.

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.