Screening of Regulatory mRNAs and miRNAs that Suppress Staphylococcus aureus Proliferation via Macrophage Ferroptosis

Ferroptosis is a unique form of regulated cell death that results from unrestricted lipid peroxidation, and it enhances the production of intracellular oxidative stress molecules. In this study, we investigated the effect of macrophage ferroptosis on the proliferation of Staphylococcus aureus (S. aureus) and sought potential host-directed therapy (HDT) targets for S. aureus. The study findings revealed that erastin concentrations (< 20 μM), which do not have an impact on macrophage proliferation, can effectively impede the proliferation of S. aureus within macrophages. High-throughput sequencing was used to identify DEGs and DEMIs in infected macrophages. Subsequently, the mRNA-miRNA regulatory network was successfully constructed, and two sets of molecules were selected. Experimental findings confirmed that mmu-miR-6935-5p exhibited complementary binding to specific sequences within the GM867 mRNA, and mmu-miR-7082-3p specifically bound to the GPR176 mRNA. Inducing ferroptosis in macrophages can effectively impede the proliferation of drug-resistant S. aureus. Notably, our study has identified GM867, GPR176, mmu-miR-6935-5p, and mmu-miR-7082-3p as key regulators involved in this process. These findings highlight the potential of targeting these four molecules for HDT, offering novel ways to combat drug-resistant S. aureus infection.