Fig. 5: Proposed effects of G6PD-d on macrophage function in ASCVD.

a G6PD-d monocytes accumulate ROS at baseline that paradoxically upregulate NOX. G6PD-d monocytes may be polarized to an M1-like phenotype characterized by the production of proinflammatory TNFɑ and MCP-1. Concurrently, reduction in M2 polarization may reduce anti-inflammatory TGFβ expression. This effect of G6PD-d would be proatherogenic though further studies are needed. b Plaque resident macrophages normally clear foam cells and debris from atherosclerotic plaques through efferocytosis, thereby preventing plaque growth and necrotic core formation. This process is inherently oxidative and relies on G6PD/PPP to maintain both redox homeostasis and continual efferocytosis. In G6PD-d, efferocytes may therefore be more prone to oxidative damage and death. Efferocyte death impairs clearance of apoptotic cells and debris while also increasing inflammation through the release of DAMPs. Further studies are needed to assess this effect in the setting of atherosclerosis.