Emerging Paradigms for Innovative Drug Discovery：Targetome and Original Combination Drugs

Chronic complex diseases，characterized by perturbations in multiple genes and pathways，have become a major challenge for both global health and innovative drug discovery. The conventional “single gene-single target-single drug” paradigm is increasingly facing limitations，as reflected by declining research and development efficiency，a slowdown in novel target discovery，and low rates of clinical translation. In parallel，combination treatment strategies，exemplified by cocktail therapies and fixed-dose combination products，have shown significant clinical efficacy. Coupled with advances in systems biology that have deepened our understanding of disease networks，these developments underscore the necessity and potential advantages of multi-target synergistic intervention. In light of current clinical needs and emerging trends in drug innovation，this article systematically presents a new paradigm centered on targetome and combination drugs. It focuses on the scope and characteristics of targetome and combination drugs，the clinical demand for combination drug development，key approaches for targetome identification and combination drug development，as well as the associated difficulties and challenges. This work aims to provide a theoretical foundation and methodological guidance for overcoming the therapeutic bottlenecks of complex diseases and for establishing a new system for original drug innovation.