Natural products as hidden molecular glues:a new framework for multi-target traditional medicinesOA

Molecular glues(MGs)are small molecules that modulate protein–protein interactions by inducing or stabilizing ternary complexes,thereby reprogramming cellular networks rather than inhibiting single targets.Natural products,shaped by evolutionary selection and characterized by exceptional structural diversity,constitute a rich and underexplored source of glue-like compounds.Here,we propose a conceptual framework for rationalizing the multi-target efficacy of traditional medicines through molecular glue mechanisms.Diverse classes of natural products,including polyketides,terpenoids,steroids,lignans,organic acids,and alkaloids,have been shown to promote proximity-driven regulation of signaling pathways and targeted protein degradation.This interaction-based mode of action provides a molecular explanation for the systems-level therapeutic effects of traditional formulations that act through multiple pathways simultaneously.Integration of molecular glue theory with network pharmacology and modern chemical biology approaches offers a strategy to decode the complex pharmacology of herbal medicines and to expand the druggable proteome.Advances in proximity-based screening technologies and machine learning are expected to further accelerate the discovery of natural product-derived molecular glues for next-generation therapeutics.