Transcriptomic and Metabolomic Profiling Identifies a Core Gene–Metabolite Axis Driving African Swine Fever Virus Replication in the Soft Tick Ornithodoros lahorensis
ABSTRACT African swine fever virus (ASFV) causes an incurable swine disease with nearly 100% mortality, posing a catastrophic threat to global pig production. The soft tick Ornithodoros lahorensis acts as a critical biological vector that sustains persistent ASFV replication and mediates long‐distance viral transmission, yet the molecular mechanisms governing ASFV‐tick interplay remain poorly understood. Here, we integrated transcriptomics and metabolomics to systematically dissect molecular changes in O. lahorensis across three infection stages: Uninfected control, early infection (7 days post‐infection, dpi), and late persistent infection (21 dpi). Multi‐omics integration revealed that ASFV extensively remodels tick host metabolism, predominantly activating purine/pyrimidine metabolism, lipid biosynthesis, and energy metabolism. We further characterized a conserved regulatory module consisting of 12 core genes and 8 signature metabolites that collectively support ASFV genome replication and virion assembly. Three hub metabolic genes (TK1, ATP5F1B, and IMPDH) were selected for functional validation via siRNA silencing in ticks; individual gene silencing suppressed ASFV loads by 89.2%, 91.5%, and 87.8%, respectively (p < 0.001***). This work represents the first comprehensive multi‐omics investigation of ASFV infection in O. lahorensis . We identified tick‐specific molecular targets to block vector‐mediated ASFV spread and established a standardized multi‐omics analytical pipeline for tick–virus interaction research. Our findings elucidate the mechanistic basis of long‐term ASFV persistence in soft ticks and deliver novel actionable clues for developing vector‐targeted ASF intervention strategies.