Geranylgeranyl diphosphate synthase deficiency impairs efferocytosis and resolution of acute lung injury.

Acute respiratory distress syndrome (ARDS) are major causes of mortality of critically ill patients. Impaired macrophage-mediated clearance of apoptotic cells (efferocytosis) in ARDS contributes to prolonged inflammation, yet the underlying mechanisms remain unclear. In this study, we investigated the role of geranylgeranyl diphosphate synthase (GGPPS) in efferocytosis during lung injury resolution. We identified dynamic changes in GGPPS expression in lung macrophages and circulating monocytes throughout the progression and resolution phases of acute lung injury (ALI). Myeloid-specific GGPPS knockout mice exhibited prolonged lung inflammation, increased accumulation of apoptotic neutrophils, a higher number of recruited macrophages, and a reduced number of resident macrophages. Notably, recruited macrophages play a dominant role in efferocytosis compared to resident macrophages. GGPPS deficiency suppressed efferocytosis in both macrophage subsets in vivo and in vitro. Mechanistically, GGPPS knockout disrupted AXL signaling in recruited macrophages. Importantly, administration of geranylgeraniol (GGOH) rescued the delayed resolution of lung injury, restored efferocytosis, and increased the suppressed AXL expression in CKO mice. Collectively, this study identifies GGPPS as a key regulator of AXL-mediated efferocytosis in recruited macrophages, highlighting its potential as a therapeutic target to accelerate ARDS resolution.