METTL3-mediated mA modification of circCSDE1 promote Coxsackievirus replication by regulating the miR-891b/BAG3 axis.

Coxsackievirus (CV), a major etiological agent of pediatric hand-foot-mouth disease and viral myocarditis, exploits host epigenetic mechanisms to facilitate pathogenesis. While N6-methyladenosine (mA) modification and circular RNAs (circRNAs) are emerging as critical regulators of viral infections, their interplay in CV pathogenesis remains unexplored. Through methylated RNA immunoprecipitation sequencing (MeRIP-seq) validation, we identified hsa_circ_0000115 (circCSDE1) as a viral-inducible circRNA significantly upregulated during CVB3 and CVA16 infection. Mechanistically, CVB infection triggered METTL3-dependent mA hypermethylation of circCSDE1 precursor RNA, enhancing its cyclization efficiency and nuclear export. Functional studies revealed that circCSDE1 acts as a competitive endogenous RNA to sequester miR-891b, thereby de-repressing BAG3 expression and activating pro-viral autophagy. CRISPR-mediated METTL3 knockout or circCSDE1 silencing markedly attenuated autophagosome formation and viral replication. This study uncovers a novel mA-circRNA regulatory axis wherein CV subverts host epitranscriptomic machinery through METTL3/circCSDE1/miR-891b/BAG3 signaling to potentiate autophagy-dependent viral propagation, providing potential therapeutic targets for enteroviral infections.