RBMX2 links Mycobacterium bovis infection to epithelial-mesenchymal transition and lung cancer progression

Tuberculosis (TB) is a complex disease caused by the interaction of pathogen, host, and environmental factors. In 2022, TB affected 10.6 million people and caused 1.3 million deaths globally. In high-burden zoonotic TB regions, Mycobacterium bovis accounts for ~10% of human TB cases. The immune evasion and latency of Mycobacterium tuberculosis hinder understanding of host responses. Here, we identify RNA-binding motif protein X-linked 2 (RBMX2) as a novel host factor facilitating M. bovis infection. RBMX2 expression is significantly upregulated in multiple cell types, including EBL, BoMac, bovine alveolar primary cells, and human A549 cells. Multi-omics analyses, cell adhesion assays, and ChIP-PCR demonstrate that RBMX2 suppresses cell adhesion and tight junctions while enhancing M. bovis adhesion and invasion via p65 signaling. Integrated transcriptomic, proteomic, and metabolomic data reveal that RBMX2 regulates epithelial-mesenchymal transition (EMT), a process linked to cancer progression. TIMER2.0 analysis shows elevated RBMX2 expression in lung adenocarcinoma and lung squamous cell carcinoma tissues, validated by immunofluorescence. Using an M. bovis-induced BoMac-EBL EMT model and H1299 cells, we show that RBMX2 promotes EMT through p65/MMP-9 pathway activation. Collectively, RBMX2 is a novel host factor that enhances M. bovis infection and drives infection-induced EMT. These findings provide new insight into TB pathogenesis and highlight RBMX2 as a potential target for TB vaccine and therapeutic development.