Targeting phenol-soluble modulin α3-driven M1 macrophage polarization and necroptosis mitigates MRSA infection in mice

The growing antibiotic resistance and high mortality rates associated with methicillin-resistant Staphylococcus aureus (MRSA) pose a global health threat, highlighting the urgent need for novel therapeutic strategies. Phenol-soluble modulin α3 (PSMα3) is a critical virulence factor in MRSA pathogenesis and immune evasion. However, its underlying mechanisms remain unclear. Here, we demonstrate that PSMα3 promotes both M1 macrophage polarization and necroptosis. These processes are mechanistically linked through an interaction between the interferon-stimulated gene factor 3 (ISGF3) and necrosome complexes, with formyl peptide receptor 2 (FPR2) serving as the key receptor. Based on this mechanism, we show that targeting signal transducer and activator of transcription 1 (STAT1), a key component of the ISGF3 complex, with the clinically approved drug fludarabine effectively mitigates MRSA infection in murine sepsis and pneumonia models. These findings reveal the mechanisms of MRSA pathogenesis and highlight the potential of anti-virulence strategies as innovative therapeutic approaches against MRSA infections.