Abstract
Background: N6-methyladenosine (m6A) modification is implicated in various diseases pathogenesis and physiological processes. We investigated the regulatory function of METTL3, a central m6A methyltransferase, in mediating m6A modification of YY1. This study aims to delineate how m6A modification of YY1 governs the pathogenesis of radiation-induced lung fibroblast injury and to elucidate its underlying molecular mechanism. Methods: The expression of METTL3 and YY1 were quantified in human lung fibroblasts and Radiation-Induced Lung Injury (RILI) mouse models. We systematically investigated whether METTL3 regulates YY1 expression through m6A-dependent mechanisms and further assessed the involvement of IGF2BP1 in modulating YY1 mRNA stability. Results: METTL3 was significantly upregulated at both transcriptional and translational levels in RILI mouse lungs and irradiated human lung fibroblasts. YY1 expression was mechanistically depended on METTL3-mediated m6A modification. METTL3 depletion attenuated RILI progression, whereas YY1 overexpression partially ameliorated this phenotype. Crucially, IGF2BP1 directly interacts with m6A-modified YY1 mRNA to influence their expression and stability. Conclusion: Our data show that METTL3-mediated m6A modification of YY1 plays a crucial role in RILI pathogenesis, and IGF2BP1 serves as an essential mediator for the stability of YY1 mRNA.