Abstract
Introduction: By pioneering the use of an 80 MeV/u 12C6+ heavy-ion beam for mutagenesis, we have engineered a stably polarized BHK-21 cell model for FMDV replication. Methods: This approach yielded two distinct clones: a highly antiviral line (BHK-5) and a highly proviral line (BHK-7). Multi-omics analyses were employed to investigate the mechanisms driving these divergent phenotypes. Results: The divergent phenotypes stem from a profound reprogramming of host transcriptional networks. The antiviral BHK-5 clone exhibits a pre-activated innate immune state, leveraging RIG-I/TLR signaling for a rapid interferon response and viral clearance via autophagy. In stark contrast, the proviral BHK-7 clone enhances glycolysis and activates the PI3K-Akt pathway to suppress TNF-mediated immunity and hijack the G2/M cell cycle phase, forming organized "virus factories." At the core of this reprogramming lies a systemic remodeling of transcription factor circuits, particularly within the Runt and C2H2 zinc-finger families. Discussion: Our work demonstrates that 12C6+ heavy-ion mutagenesis can rewire the host immunity-metabolism-cell cycle axis to dictate infection outcomes, providing a powerful framework and cellular toolkit for developing high-yield vaccine substrates and novel antiviral strategies.