This study investigates the mechanism by which Brucella ovis evades host clearance. Using integrative multi-omics analysis (transcriptome, proteome, and lncRNAome), we identified a novel regulatory axis where lncRNA 225639 negatively regulates autophagy in RAW264.7 macrophages by modulating Cathepsin B (Ctsb) expression, thereby promoting intracellular bacterial survival.