Macrophage ferroptosis potentiates GCN2 deficiency induced pulmonary venous arterialization

Jingyuan Zhang, Pei Mao, Tengfei Zhou, Bingqing Yue, Yaning Li, Yuanhua Qiu, Kejing Ying, Fudi Wang, Jingyu Chen and Jun Yang ()
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Jingyuan Zhang: Zhejiang University School of Medicine
Pei Mao: Zhejiang University School of Medicine
Tengfei Zhou: Zhejiang University School of Medicine
Bingqing Yue: Zhejiang University School of Medicine
Yaning Li: Zhejiang University School of Medicine
Yuanhua Qiu: Zhejiang University School of Medicine
Kejing Ying: Zhejiang University School of Medicine
Fudi Wang: Department of Public Health of Zhejiang University School of Medicine
Jingyu Chen: Zhejiang University School of Medicine
Jun Yang: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Pulmonary veno-occlusive disease (PVOD) is a fatal disease characterized by the remodelling of pulmonary veins and haemosiderin accumulation in macrophages. Although (General Control Nonderepressible 2) GCN2 deficiency has been reported in PVOD patients, the underlying mechanism by which GCN2 deficiency affects the pulmonary venous cells and the surrounding cells, remains unclear. Here, we perform immunohistochemistry and scRNA-sequencing analyses to show that macrophages are the major population affected by GCN2 deficiency and ferroptosis pathway-related genes are upregulated in lung macrophages of PVOD patients. Treatment with the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) reverses the changes in haemodynamic indices observed in Eif2ak4K1488X/K1488X hypoxia mice and PVOD model rats. Furthermore, GCN2 deficiency increases HMOX1 and iron levels to facilitate ferroptosis in macrophages, and enhances arterial marker expression in venous endothelial cells (VECs). Specifically, spatial transcriptome analysis shows increased expression of NRP1, KDR and EFNB2 through ETS1 in VECs from PVOD patients. Our findings suggest the potential of targeting macrophage ferroptosis as a therapeutic strategy for treating related vascular diseases, and of using NRP1/KDR/EFNB2 expression as a specific marker set for venous arterialization.

Date: 2025
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DOI: 10.1038/s41467-025-64035-4

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