Macrophage USF2 Lactylation‐Mediated FABP4 Suppression Promotes Intracellular Proliferation of Brucella

Brucella spp. are facultative intracellular bacteria that infect and induce brucellosis in a diverse range of mammalian hosts. Understanding the mechanisms underlying the intracellular survival of Brucella is of critical importance for the prevention and control of brucellosis. This study uncovers the mechanism by which Brucella abortus manipulates host lactate metabolism to facilitate its intracellular proliferation. Infection of macrophages by B. abortus enhanced L‐lactate production by the host macrophages, which in turn promoted bacterial proliferation. Proteomic and functional analyses identified the host glucose transporter protein Slc2a1 as a positive regulator of both B. abortus proliferation and host cellular lactylation. The B. abortus effector protein SepA upregulated Slc2a1 expression and host cellular lactylation. Lactylation of the transcription factor USF2 at lysine residues 255 and 275 suppressed production of the host lipid metabolism‐associated protein Fabp4, thereby enhancing bacterial survival. Moreover, Fabp4 inhibition attenuated B. abortus ‐induced M1 polarization and lipid metabolism in macrophages. These findings reveal a dual‐axis regulatory network through which B. abortus exploits host L‐lactate metabolic reprogramming via the SepA/Slc2a1 and L‐lactate‐USF2/Fabp4 axes to establish its intracellular niche, providing new insights into host– Brucella metabolic crosstalk.