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However, target identification remains a major bottleneck in natural product\u2010based drug discovery, largely because of the chemical complexity of natural products and the heterogeneity of biological systems. To address these challenges, various complementary strategies have been developed, including experimental strategies such as chemical proteomics, and computational methods such as artificial intelligence\u2010driven methods. Nevertheless, reliably advancing a candidate protein hit to a therapeutically relevant and physiologically validated target remains a critical challenge. Focusing on technologies for natural product target discovery, this review systematically summarizes the principles, methodologies, and practical applications of current approaches. Through representative case studies, we further propose a reusable integrated experimental\u2013computational workflow and illustrates how key targets and their modes of action can be identified in real\u2010world research scenarios. In addition, we discuss common technical and conceptual bottlenecks encountered during target discovery and proposes potential countermeasures. The review provides an actionable reference framework for natural product target identification, with the goal of reducing false\u2010positive findings and fragmented evidence, thereby improving the robustness of mechanism\u2010oriented studies and facilitating subsequent translational research.<\/jats:p>","DOI":"10.1002\/mco2.70777","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:31:18Z","timestamp":1779690678000},"source":"Crossref","is-referenced-by-count":4,"title":["Progress in Natural Products Target Discovery Technology"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2567-3206","authenticated-orcid":false,"given":"Qiyuan","family":"Pan","sequence":"first","affiliation":[{"name":"Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital Shanghai University of Traditional Chinese Medicine  Shanghai 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