{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:20:00Z","timestamp":1790306400809,"version":"4.1.0"},"reference-count":62,"publisher":"National Academy of Sciences","issue":"16","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22176229"],"award-info":[{"award-number":["22176229"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21976216"],"award-info":[{"award-number":["21976216"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3905202"],"award-info":[{"award-number":["2023YFC3905202"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3708304"],"award-info":[{"award-number":["2023YFC3708304"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"MOE | Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["23xkjc007"],"award-info":[{"award-number":["23xkjc007"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:p>\n                    Ischemic retinal diseases are major causes of blindness worldwide and are characterized by pathological angiogenesis. Epigenetic alterations in response to metabolic shifts in endothelial cells (ECs) suffice to underlie excessive angiogenesis. Lactate accumulation 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&amp;Tag and scRNA-seq analyses identified\n                    <jats:italic>Prmt5<\/jats:italic>\n                    as a target of H3K9la and H3K18la in isolated retinal ECs. EC-specific deletion of\n                    <jats:italic>Prmt5<\/jats:italic>\n                    since the early stage of revascularization suppressed a positive feedback loop of lactate production and histone lactylation, thus inhibiting neovascular tuft formation. Mechanistically, the C-terminal intrinsically disorder region (IDR) of the transmembrane semaphorin 6A (SEMA6A) forms liquid\u2013liquid phase separation condensates to recruit RHOA and P300, facilitating P300 phosphorylation and histone lactylation cycle. Deletion of endothelial\n                    <jats:italic>Sema6A<\/jats:italic>\n                    reduced H3K9la and H3K18la at the promoter of\n                    <jats:italic>PRMT5<\/jats:italic>\n                    and diminished its expression. The induction of histone lactylation by SEMA6A-IDR and its pro-angiogenic effect were abrogated by deletion of\n                    <jats:italic>Prmt5<\/jats:italic>\n                    . Our study illustrates a sustainable histone lactylation machinery driven by phase separation-dependent lactyltransferase activation in dysregulated vascularization.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2423677122","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T11:47:36Z","timestamp":1744890456000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":30,"title":["Semaphorin 6A phase separation sustains a histone lactylation\u2013dependent lactate buildup in pathological angiogenesis"],"prefix":"10.1073","volume":"122","author":[{"given":"Ya","family":"Ma","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolian","family":"Cao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianlei","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuting","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijing","family":"Xie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjuan","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junru","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxin","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Hao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiali","family":"Zhong","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Ju","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6103-1498","authenticated-orcid":false,"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunqiao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3398-5657","authenticated-orcid":false,"given":"Yanhong","family":"Wei","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay5356"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93751"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1208129"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60178-6"},{"key":"e_1_3_4_5_2","first-page":"17","article-title":"Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss","volume":"2","author":"Lee R.","year":"2015","unstructured":"R. Lee, T. Y. Wong, C. Sabanayagam, Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis. (London, England) 2, 17 (2015).","journal-title":"Eye Vis. (London, England)"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42142"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1301021"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1512683112"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf9440"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.15217"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.26074"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00631-w"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2024.07.008"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129862"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2017234117"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.08.011"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12240"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1523005113"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.129398"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00551-2"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-020-09760-8"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.187"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-311589"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2023.11.018"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2249762"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.06.013"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.320488"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-024-03308-5"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44321-024-00025-1"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07992-y"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06187-z"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.152481"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022019419"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.42047"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.53023"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abi6696"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2023.106135"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44900"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-0126"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-02-410076"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.027"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.09.002"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2022.07.004"},{"key":"e_1_3_4_44_2","first-page":"916","article-title":"High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers","volume":"60","author":"Walenta S.","year":"2000","unstructured":"S. Walenta , High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 60, 916\u2013921 (2000).","journal-title":"Cancer Res."},{"key":"e_1_3_4_45_2","first-page":"383","article-title":"The angiogenic switch leads to a metabolic shift in human glioblastoma","volume":"19","author":"Talasila K. M.","year":"2017","unstructured":"K. M. Talasila , The angiogenic switch leads to a metabolic shift in human glioblastoma. Neuro-oncology 19, 383\u2013393 (2017).","journal-title":"Neuro-oncology"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-023-02931-y"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2024.07.004"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01856-1"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.03.008"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202301300"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-28215-w"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.02.015"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510954200"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.042"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2023.01.005"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2022.11.009"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-023-01580-8"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158686"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2215828120"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.05.014"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"e_1_3_4_62_2","unstructured":"Y. Wei Semaphorin 6A phase separation sustains a histone lactylation dependent lactate buildup in pathological angiogenesis. Genome Sequence Archive. https:\/\/ngdc.cncb.ac.cn\/gsa\/search?searchTerm=CRA024243. Deposited 29 March 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2423677122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T11:48:33Z","timestamp":1744890513000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2423677122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,17]]},"references-count":62,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2025,4,22]]}},"alternative-id":["10.1073\/pnas.2423677122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2423677122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,17]]},"assertion":[{"value":"2024-11-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2423677122"}}