Monocyte histone lactylation-regulated exosomal periostin promotes retinal neovascularization

Exosomes serve as signaling messengers that facilitate intercellular communication through delivering molecular cargo. Here, we observed elevated levels of exosomal periostin (POSTN) in blood plasma of patients with proliferative diabetic retinopathy (PDR). Monocytes-derived exosomal POSTN was increased under high glucose condition, and deletion of Postn in myeloid cells reduced retinal neovascularization. Monocytes isolated from the blood of PDR patients exhibited heightened glycolytic activity and elevated histone lactylation levels, particularly H4K8 lactylation (H4K8la). Knockout of Hexokinase 2 (Hk2) in myeloid cells led to reduced H4K8la and POSTN levels and inhibited retinal neovascularization. Exogenous exosomal POSTN partially reversed the angiogenic defects caused by Postn or Hk2 deletion in myeloid cells. Mechanistically, exosomal POSTN stabilized hypoxia-inducible factor 1-alpha (HIF1-a) and upregulated the expression of angiogenic genes. Notably, treatment with metformin reduced retinal neovascularization by decreasing monocytes glycolysis and lowering exosomal POSTN levels. In summary, these findings underscore the critical role of circulating exosomal POSTN in retinal neovascularization and highlight its potential as a therapeutic target for angiogenic retinopathies.