S100A4 regulates ferroptosis to suppress cell proliferation via the SLC7A11-GSH axis but facilitates Brucella infection in RAW264.7 macrophages.

S100A4 is a low-molecular-weight protein belonging to the S100 protein family, and is widely expressed in a variety of cells. It plays important regulatory roles in cell physiological processes, including proliferation, adhesion, motility, and the inflammatory and immune responses. In this study, we investigated the roles of S100A4 in host cell proliferation and Brucella infection. We found that Brucella inhibited S100A4 expression in RAW264.7 macrophages in a late stage of infection. Knockout of S100A4 expression significantly enhanced the proliferation of RAW264.7 macrophages, whereas the overexpression of S100A4 inhibited their proliferation. A proteomic analysis indicated that the overexpression of S100A4 in RAW264.7 macrophages affected pathogen infection, signaling pathway regulation, cell mobility and adhesion, and the ferroptosis pathway. We also found that the role of S100A4 in the proliferation of RAW264.7 macrophages is ferroptosis dependent. Fer-1 treatment increased the proliferation of S100A4(OE) cells, which was mediated by the ATF4-SLC7A11-GSH axis. The overexpression of S100A4 promoted the intracellular infection of Brucella, with enhanced bacterial intracellular survival and adhesion, in RAW264.7 macrophages. In summary, we have demonstrated that S100A4 plays vital roles in the growth of RAW264.7 macrophages and an important role in Brucella intracellular infection by enhancing the pathogen's intracellular viability and adhesion ability.