Coordinated inhibition of M1 macrophage polarization by FIT2-mediated lipid droplet biosynthesis and FABP5

Lipid droplets (LDs) serve as dynamic organelles central to host immune response and bacterial infection resistance by recruiting multiple proteins and peptides with established antiviral and antibacterial properties. Although macrophage polarization is integral to both innate immunity and lipid homeostasis, the regulatory influence of LDs on this process remains unclear. In this study, augmentation of LDs via oleic acid (OA) treatment attenuated M1 polarization in RAW264.7 macrophages. Given that LD budding is mediated by fat storage-inducing transmembrane protein 2 (FIT2) encoded by FITM2, transcriptomic analysis following FITM2 knockdown revealed suppressed expression of fatty acid-binding protein 5 (FABP5), a lipid-binding protein that further modulated LD abundance. Both FIT2 and FABP5 were found to regulate LD content and collectively contributed to inhibition of M1 macrophage polarization. This shift impaired macrophage capacity to mount effective antibacterial responses. These findings identify a coordinated role for LDs and FABP5 in modulating M1 macrophage polarization, establishing a mechanistic link between lipid metabolism and innate host defense against bacterial infection.