SRPX2 Regulates Macrophage Antibacterial Defense via the PI3K/AKT–NOX2–ROS–LAP Pathway During Staphylococcus aureus Infection

Methicillin-resistant S. aureus (MRSA) strains remain a critical clinical threat due to their broad antibiotic resistance, highlighting an urgent demand for innovative therapeutic strategies. In this study, we identified Sushi repeat-containing protein X-linked 2 (SRPX2) as a novel regulator governing macrophage antibacterial defense.

Our results demonstrate that SRPX2 is rapidly upregulated upon S. aureus infection and functions as an upstream activator of the PI3K/AKT signaling cascade. This signaling axis is essential for NOX2 activation and the subsequent generation of reactive oxygen species (ROS), which further facilitate LC3-associated phagocytosis (LAP), a non-canonical autophagy pathway indispensable for efficient bacterial clearance. SRPX2 deficiency compromises ROS production and LAP activation, thereby promoting intracellular bacterial survival and underscoring the pivotal role of SRPX2 in macrophage antimicrobial defense.