Abstract
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.