From Rational Design to Clinical Translation：Current Status and Future Perspectives of Multi-target Small-molecule Drugs

Complex diseases are often driven by aberrations in multi-level and multi-pathway molecular networks. Consequently，traditional drug discovery paradigms centered on single targets have increasingly revealed limitations in terms of durable efficacy and resistance control. In this context，multi-target single-molecule drugs capable of simultaneously modulating multiple key pathological nodes have emerged as a promising strategy in innovative drug development，owing to their intrinsic synergistic potential and advantages in systems-level intervention. With rapid advances in molecular biology，systems pharmacology，and computational chemistry，the conceptual framework for multi-target drug design has evolved from empirical discovery toward mechanism-guided，data-integrated rational design. This review systematically summarizes the design strategies，technological advances，and current clinical applications of multi-target small-molecule drugs，as well as the key challenges associated with their development. Furthermore，by integrating emerging technologies such as artificial intelligence，genome editing，and computational biology，we discuss future directions and opportunities for multi-target drug development in areas including cancer，neurodegenerative disorders，and metabolic syndrome.