A novel mechanism of radiation-induced lung injury: METTL3 mediates fibrogenesis through N6-methyladenosine modification of YY1.

BACKGROUND

N6-methyladenosine (mA) modification is implicated in various diseases pathogenesis and physiological processes. We investigated the regulatory function of METTL3, a central mA methyltransferase, in mediating mA modification of YY1. This study aims to delineate how mA 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 mA-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 mA modification. METTL3 depletion attenuated RILI progression, whereas YY1 overexpression partially ameliorated this phenotype. Crucially, IGF2BP1 directly interacts with mA-modified YY1 mRNA to influence their expression and stability.

CONCLUSION

Our data show that METTL3-mediated mA modification of YY1 plays a crucial role in RILI pathogenesis, and IGF2BP1 serves as an essential mediator for the stability of YY1 mRNA.