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Their aberrant activation drives malignancies, fibrosis, cardiovascular disease, and immune dysregulation. Once regarded undruggable, the YAP\/TAZ\u2013TEAD complex has become one of the most actively pursued target classes in oncology and beyond. In this review, we delineate the biological functions of the Hippo\u2013YAP\/TAZ\u2013TEAD axis and integrate its pathway physiology with the structural basis of druggability, centered on the \u03a9\u2010loop surface pocket and the buried palmitoylation\u2010binding pocket (PBP) of TEAD, whose distinct geometries dictate the pharmacophoric requirements, paralog selectivity, and resistance liabilities of current agents. We then systematically compare mechanism\u2010guided therapeutic modalities, encompassing direct protein\u2013protein interaction disruptors, covalent and noncovalent PBP inhibitors, proteolysis\u2010targeting chimeras (PROTACs), and cofactor\u2010interface modulators. We also analyze the upstream kinase (MST1\/2, LATS1\/2) modulators, direct YAP\/TAZ inhibitors and degraders, and emerging gene\u2010, RNA\u2010, antibody\u2010, and cell\u2010based therapies. We critically evaluate preclinical and early clinical performance across oncology, fibrosis, immunology, and regenerative medicine, distinguishing robust proof\u2010of\u2010concept from clinically meaningful benefit. We further dissect resistance mechanisms, on\u2010target safety concerns, and the therapeutic\u2010window limitations of pan\u2010TEAD inhibition. Ultimately, we outline rational combination strategies, biomarker\u2010guided patient selection, and future directions for paralog\u2010selective and tissue\u2010restricted Hippo\u2010targeted therapeutics.<\/jats:p>","DOI":"10.1002\/mco2.71027","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:42:22Z","timestamp":1790149342000},"source":"Crossref","is-referenced-by-count":0,"title":["Hippo Pathway\u2013YAP\/TAZ Signaling: Molecular Mechanisms, Biological Function, Diseases, and Therapeutic Targets"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5696-4824","authenticated-orcid":false,"given":"Xiaodan","family":"Qu","sequence":"first","affiliation":[{"name":"Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University Shenyang PR 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