ArticleScience advances2025
AI-driven discovery of dual antiaging and anti-AD therapeutics via PROTAC target deconvolution of a super-enhancer-regulated axis.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
4 citing papers in PubMed.
- Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems.Acta pharmacologica Sinica · 2026Review
- P53 Competitively Binds P300 to Suppress HIF-1α/TFRC-Mediated Ferroptosis and Promote Doxorubicin Resistance in Breast Cancer.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Target discovery and drug design in the era of artificial intelligence.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Decoding Vascular Senescence: Cellular Insights and Therapeutic Strategies.International journal of biological sciences · 2026Review
Corrections and comments
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Authors and funding
20 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The lack of safe, durable therapeutics that act against both biological aging and Alzheimer's disease is an unmet clinical need. To bridge this gap, we devised an artificial intelligence (AI)-enabled 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)-guided chemoproteomic deconvolution next pinpointed the histone acetyltransferase p300 as MLT's 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-centric mechanistic resolution, our study identifies MLT as a dual-action candidate and sets out a reproducible "AI-to-clinic" paradigm for multitarget drug innovation in aging-related neurodegeneration.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.