Targeting Complexity：Scientific Foundation and Frontiers of Multi-target Drug Discovery

In recent years，multi-target drugs have emerged as an innovative strategy to address the multifactorial pathological mechanisms of complex diseases，representing a promising direction for precision medicine. This review systematically traces the evolution of multi-target drug discovery，from early serendipitous findings to contemporary rational design approaches. It highlights representative advances in the fields of oncology，metabolic disorders，and neuropsychiatric diseases，with a focus on the molecular basis of target synergy，logical principles for target combination selection，and the integrated application of artificial intelligence （AI） and structural biology in drug design. Building on these developments，we further analyze key scientific challenges that remain to be overcome，including accurate prediction of target interactions，optimization of drug-likeness and selectivity，identification of resistance mechanisms，and translational research bottlenecks. Finally，we propose future research directions，emphasizing the importance of interdisciplinary collaboration and the integration of basic and applied research to drive innovation in multi-target drug discovery. This review aims to provide a theoretical foundation and practical guidance for the systematic development of combination-targeted therapeutics，thereby contributing to the establishment of a new paradigm for effective intervention in complex diseases.