Macrophage ferroptosis potentiates GCN2 deficiency induced pulmonary venous arterialization

Haemosiderin-laden macrophages and the remodeling of pulmonary venules were found in Pulmonary veno-occlusive disease (PVOD), which is a fatal pulmonary vascular disease with deficient GCN2 expression, the underlying mechanism by which macrophage affects vascular cells, remains unclear. Here, we performed scRNA-sequencing analyses to show that macrophages were the major population affected by GCN2 deficiency and ferroptosis pathway-related genes were upregulated in lung macrophages from PVOD patients. Treatment with the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed the changes in haemodynamic indices observed in Eif2ak4K1488X/K1488X hypoxia mice and PVOD model rats. Furthermore, GCN2 deficiency increased HMOX-1 and iron levels to facilitate ferroptosis in macrophages and increased GCN2 deficiency-induced arterial marker expression in venous endothelial cells (VECs). Our findings suggest the potential of targeting macrophage ferroptosis as a therapeutic strategy for treating PVOD.