An 8-gene host-derived signature (<i>ARHGEF5, PTGES3L, GAL3ST1, RANBP17, ACTA2_AS1, CBY3, MAMSTR, and LOC102031319</i>) discriminated DR-TB from DS-TB with high accuracy (AUC = 0.837).<h4>Conclusion</h4>This dual-omics study defines the airway niche of DR-TB as a convergence of microbial dysbiosis, phage imbalance, and host immune-metabolic dysfunction. The gene discussed is RANBP17; the disease is tuberculosis.