AI-driven discovery of dual antiaging and anti-AD therapeutics via PROTAC target deconvolution of a super-enhancer-regulated axis.

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 Tagmentati

SUBMITTER: Sun Y 

PROVIDER: S-EPMC12629202 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature