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

Abstract

BACKGROUNDRadiation therapy for cancer treatment frequently leads to radiation-induced heart disease (RIHD), characterized as cardiac fibrosis and heart failure. The enzyme METTL3, a key player in RNA methylation, is known to influence various cellular processes, while its specific role and mechanism in RIHD are not well understood. OBJECTIVESThe purpose of this study was to explore the potential mechanism of METTL3 in regulating cardiac fibrosis induced by radiation. METHODSWe constructed an X-ray-modulated RIHD mice models to investigate the role of METTL3 in cardiac fibroblasts. In parallel, METTL3 overexpression and silence were conducted on fibroblasts and mice heart to evaluate pro-fibrotic protein expression, cardiac fibrosis, and heart function. RESULTSElevated METTL3 expression was observed in both irradiated cardiac tissues and fibroblasts. Moreover, overexpression of METTL3 in cardiac fibroblasts was associated with increased expression of pro-fibrotic proteins and exacerbated fibrosis, whereas METTL3 silencing attenuated these adverse effects. Likewise, METTL3 knockdown ameliorated cardiac dysfunction and reduced fibrosis. Taken together, METTL3 could induce cardiac fibrosis via activating the Akt/mTOR signaling pathway to promote fibroblast proliferation and myofibroblast differentiation. CONCLUSIONSMETTL3 is a critical of RICD through modulating the Akt/mTOR pathway, hence targeting METTL3 presents a promising therapeutic strategy to mitigate the adverse cardiac effects of radiation therapy in cancer patients.