{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:43:35Z","timestamp":1792205015338,"version":"4.4.0"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"47","funder":[{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzhen","doi-asserted-by":"publisher","award":["SZSM202301035"],"award-info":[{"award-number":["SZSM202301035"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2632025ZD10"],"award-info":[{"award-number":["2632025ZD10"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"the China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2024T171037"],"award-info":[{"award-number":["2024T171037"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Young Elite Scientists Sponsorship Program by CAST","award":["2024-2026QNRC001"],"award-info":[{"award-number":["2024-2026QNRC001"]}]},{"name":"Haihe Laboratory of Cell Ecosystem Innovation Fund","award":["22HHXBSS00005"],"award-info":[{"award-number":["22HHXBSS00005"]}]},{"name":"Postdoctoral Excellence Program of Jiangsu Province","award":["2022ZB297"],"award-info":[{"award-number":["2022ZB297"]}]},{"name":"Key Project of Basic Research Program of Jiangsu Province","award":["BK20243061"],"award-info":[{"award-number":["BK20243061"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,11,21]]},"abstract":"<jats:p>The lack of safe, durable therapeutics that act against both biological aging and Alzheimer\u2019s disease is an unmet clinical need. To bridge this gap, we devised an artificial intelligence (AI)\u2013enabled approach that pairs rapid compound triage with mechanistic target deconvolution. Our AI-driven screening highlighted melatonin (MLT) as a promising candidate. Serum profiling of 161 human individuals confirmed an age-related fall in circulating MLT level, while subsequent in vivo and in vitro experiments showed that MLT rescues cognition, suppresses neuroinflammation, and alleviates senescence phenotypes. Proteolysis targeting chimera (PROTAC)\u2013guided chemoproteomic deconvolution next pinpointed the histone acetyltransferase p300 as MLT\u2019s target. Integrated Cleavage Under Targets and Tagmentation, single-cell RNA sequencing, and spatial transcriptomics revealed that MLT-bound p300 cooperates with specificity protein 1 (SP1) at a brain and muscle ARNT-like protein 1 super-enhancer, elevating histone H3 lysine-27 acetylation and reengaging a circadian-epigenetic program that links redox resilience to neuroprotection. By combining AI-driven discovery with PROTAC-based target mapping and super-enhancer\u2013centric mechanistic resolution, our study identifies MLT as a dual-action candidate and sets out a reproducible \u201cAI-to-clinic\u201d paradigm for multitarget drug innovation in aging-related neurodegeneration.<\/jats:p>","DOI":"10.1126\/sciadv.adz9283","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:58:54Z","timestamp":1763578734000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["AI-driven discovery of dual antiaging and anti-AD therapeutics via PROTAC target deconvolution of a super-enhancer\u2013regulated axis"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5216-7899","authenticated-orcid":true,"given":"Yuan","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0820-3465","authenticated-orcid":true,"given":"Sai","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0102-2692","authenticated-orcid":true,"given":"Long","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5028-4530","authenticated-orcid":true,"given":"Zheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Computer Science, RWTH Aachen University, Aachen 52074, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinran","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tucheng","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anbo","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beiyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2112-0510","authenticated-orcid":true,"given":"Xinai","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2135-3812","authenticated-orcid":true,"given":"Zheying","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8297-1921","authenticated-orcid":true,"given":"Guangji","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3455-1955","authenticated-orcid":true,"given":"Xinuo","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","unstructured":"United Nations World Population Prospects 2024 (2024); https:\/\/population.un.org\/wpp\/."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.019"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI158453"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12385"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt269"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.021"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254403"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3569"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09817"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00314-w"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1252945"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-5-51"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-019-0132-6"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.07.014"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-024-00397-x"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01356-x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0190-z"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-024-00797-y"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smrv.2025.102121"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-022-01897-y"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30461-7"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah4968"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102699"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00728"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21330-0"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00774-7"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32326-9"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-00946-z"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42256-020-00285-9"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4896"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1041610216002131"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2018.06.011"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-025-04992-5"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)70016-5"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00823-1"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-024-02820-x"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2693"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-024-00727-x"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-07-746396"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e11-10-0884"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201700247"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2022.07.007"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac394"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21162"},{"key":"e_1_3_2_46_2","unstructured":"L. Wu Y. Tian Y. Huang S. Li H. Lin N. V. Chawla S. Z. Li MAPE-PPI: Towards effective and efficient protein-protein interaction prediction via microenvironment-aware protein embedding. arXiv: 2402.14391 [cs.LG] (2024)."},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115521"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02261-x"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-020-00124-9"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.10.003"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2007.02.003"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.040"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2023.1069155"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13704"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-021-00788-6"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2020.135192"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-150161"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12248"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/biof.1369"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/gps.4571"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afad104.088"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.04.034"},{"key":"e_1_3_2_63_2","first-page":"947","article-title":"Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer\u2019s disease: A 6-month, randomized, placebo-controlled, multicenter trial","volume":"9","author":"Wade A. G.","year":"2014","unstructured":"A. G. Wade, M. Farmer, G. Harari, N. Fund, M. Laudon, T. Nir, A. Frydman-Marom, N. Zisapel, Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer\u2019s disease: A 6-month, randomized, placebo-controlled, multicenter trial. Clin. Interv. Aging 9, 947\u2013961 (2014).","journal-title":"Clin. Interv. Aging"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.73223"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.50.1.387"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.101928"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.02.003"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-023-02614-z"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14436"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202308970"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac357"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01091-3"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3317"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw257"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1322"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab996"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac947"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adz9283","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:59:10Z","timestamp":1763578750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adz9283"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":80,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2025,11,21]]}},"alternative-id":["10.1126\/sciadv.adz9283"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adz9283","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]},"assertion":[{"value":"2025-06-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadz9283"}}