Endothelial AGGF1 promotes retinal angiogenesis by coordinating TNFSF12/FN14 signalling

Ying Cheng, Man Zhang, Chenguang Li, Long Su, Lingli Fu, Shi Wu, Chaofei Xu, Bei Sun () and Liming Chen ()
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Ying Cheng: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Man Zhang: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Chenguang Li: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Long Su: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Lingli Fu: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Shi Wu: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Chaofei Xu: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Bei Sun: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
Liming Chen: Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Abnormal angiogenesis is a key process associated with ischaemic retinopathies such as diabetic retinopathy, for which the underlying pathological mechanisms are still poorly understood. Here, we confirm that angiogenic factor 1 with a G patch and FHA domain (AGGF1) is elevated in the diabetics and induces retinal angiogenesis. Mechanistic investigations demonstrate that HIF-1α directly regulates AGGF1 expression. AGGF1 upregulates the expression of cell cycle proteins by increasing the binding of tumour necrosis factor ligand superfamily member 12 (TNFSF12) to fibroblast -growth -factor-inducible 14 (FN14, TNFRSF12A). Furthermore, targeting AGGF1 attenuates pathological neovascularisation in ischaemic retinopathy. Additionally, we discover that sodium-glucose cotransporter 2 inhibitors (SGLT2i) could inhibit the AGGF1 signalling pathway early to achieve therapeutic effects. Overall, we elucidate the mechanism underlying pathological retinal angiogenesis involved in endothelial AGGF1-dependent events and highlight a therapy for the effective treatment of ischaemic retinopathy.

Date: 2025
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DOI: 10.1038/s41467-025-55970-3

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