Lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis

作者：Mao Zhao, Yuxuan Qian, Lin He, Tao Peng, Hanbin Wang, Xiangxu Wang, Lin Jiang, Jinrong Fan, Hengxiang Zhang, Di Qu, Qing Zhu, Hao Wang, Shida Zhang, Chenyang Li, Chenyang Li, Xiwen Dong, Xianya Zhao, Huina Wang, Yuqi Yang, Xiuli Yi, Tao Zhao, Yu Liu, Guoqiang Zhang, Guoqiang Zhang, Qiong Shi, Tianwen Gao, Chunying Li, Chunying Li, Weinan Guo · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-08023-y · 被引用次数：14 · 研究领域：Immune cells in cancer、Epigenetics and DNA Methylation、IL-33, ST2, and ILC Pathways

The pathogenesis of cancer is complicated, with metabolic reprogramming and angiogenesis as the hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation to epigenetically regulate gene expressions and biological processes in cancer, while the effect on tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we first proved that lactate and histone lactylation facilitated melanoma angiogenesis both in vitro and in vivo. Then, through RNA-sequencing and a series of biochemical assays, we found that lactate promoted the transcription of suppression of tumorigenicity 2 (ST2) in tumor-associated endothelial cells via the enhancement of histone lactylation at its promoter, so that to increase the response of endothelial cells to pro-angiogenic interleukin-33 (IL-33) stimulation. In addition, lactate could also suppress high endothelial venules transition of endothelial cells, which was critical for tumor development. Ultimately, the effect of anti-angiogenic drug synergized with lactate dehydrogenase (LDH) inhibition/ST2 inhibition on melanoma growth was proved in vivo. Taken together, we demonstrated that lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis, which delineated a novel regulatory relationship among lactate, histone lactylation and angiogenesis in cancer, and provided a promising combined therapeutic strategy to target angiogenesis from the...