Semaphorin 6A phase separation sustains a histone lactylation-dependent lactate buildup in pathological angiogenesis

• 成果类型: Article
• 署名作者: Ma, Ya; Zhang, Zhuyi; Cao, Xiaolian; Guo, Dianlei; Huang, Shuting; Xie, Lijing; Wu, Mingjuan; Li, Junru; Li, Chenxin; Chu, Yu; Jiang, Shuxin; Hao, Yu; Wang, Can; Zhong, Xiali; Ju, Rong; Zhang, Feng; Liu, Chunqiao; Wei, Yanhong
• 署名单位: Sun Yat Sen University; Sun Yat Sen University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11971
• DOI: 10.1073/pnas.2423677122
• 发表日期: 2025-04-22
• 关键词: retinopathy

摘要

Ischemic retinal diseases are major causes of blindness worldwide and are characterized by pathological angiogenesis. Epigenetic alterations in response to metabolic shifts in and its subsequent histone lactylation in ECs contribute to vascular disorders. However, the regulatory mechanism of establishing and sustaining lactylation modification remains elusive. Here, we showed that lactate accumulation induced histone lactylations on H3K9 and H3K18 in neovascular ECs in the proliferative stage of oxygen- induced retinopathy. Joint CUT&Tag and scRNA- seq analyses identified Prmt5 as a target of early stage of revascularization suppressed a positive feedback loop of lactate production and histone lactylation, thus inhibiting neovascular tuft formation. Mechanistically, yltransferase activation in dysregulated vascularization.