YY1 Lactylation in Microglia Promotes Angiogenesis Through Transcription Activation-Mediated Upregulation of FGF2

Ocular neovascularization is a leading cause of blindness. Retinal microglia have been implicated in hypoxia-induced angiogenesis and vasculopathy, but the underlying mechanisms remain largely unknown. Here, we report that lactylation in microglia is critical for retinal neovascularization. Using lactylome and proteomic analyses, we identified a list of hyperlactylated proteins in the context of increased lactate under hypoxia. Our results show that Yin Yang-1 (YY1), a transcription factor, is lactylated at lysine 183 (K183) under hypoxia, which is regulated by p300. Furthermore, hyperlactylated YY1 directly enhances fibroblast growth factor 2 (FGF2) transcription and promotes angiogenesis. YY1 mutation at K183 eliminates these effects. Notably, the administration of p300 inhibitor A485 greatly suppresses vascularization in vivo and in vitro. Taken together, our results demonstrate that YY1 lactylation in microglia promotes FGF2 expression and plays a pivotal proangiogenic role, providing new insights into retinal neovascular diseases.