Background: Nontuberculous mycobacteria (NTM) and Mycobacterium tuberculosis (TB) pulmonary infections share clinical features but have divergent outcomes, suggesting distinct host immune adaptations. Methods: We integrated transcriptomic datasets (GSE97298: 32 NTM vs. 9 controls; GSE83456: 45 TB vs. 61 controls) to identify shared and distinct molecular pathways. Differentially expressed genes (DEGs) were analyzed via limma (|log2FC| ≥ 1.5, FDR < 0.05), with functional enrichment (WebGestalt/Metascape) and PPI networks (STRING/Cytoscape). Results: We identified 48 shared DEGs with bidirectional regulation (e.g., LDHB: NTM ↓ vs. TB ↑; NOD2: NTM ↑ vs. TB ↓). Pathway analysis revealed neutrophil degranulation as a core-shared mechanism (FDR = 2.37 × 10？6). ELANE and DEFA4 showed strong co-expression (Spearman *r* = 0.86, *p* < 0.001) linking to NETosis, while IRAK3 (innate immunity hub) and CD28 (adaptive node) emerged as context-dependent regulators. Conclusion: This study defines conserved neutrophil-driven immunopathology in mycobacterial infections and nominates IRAK3/CD28 for host-directed therapies.
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