Hippo Pathway-YAP/TAZ Signaling: Molecular Mechanisms, Biological Function, Diseases, and Therapeutic Targets

The Hippo pathway and its downstream effectors Yes-associated protein/transcriptional coactivator with PDZ-binding motif-TEA domain transcription factor (YAP/TAZ-TEAD) play critical roles in organ-size control, tissue homeostasis, regeneration, and stem-cell biology. Their aberrant activation drives malignancies, fibrosis, cardiovascular disease, and immune dysregulation. Once regarded undruggable, the YAP/TAZ-TEAD 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-YAP/TAZ-TEAD axis and integrate its pathway physiology with the structural basis of druggability, centered on the Ω-loop surface pocket and the buried palmitoylation-binding pocket (PBP) of TEAD, whose distinct geometries dictate the pharmacophoric requirements, paralog selectivity, and resistance liabilities of current agents. We then systematically compare mechanism-guided therapeutic modalities, encompassing direct protein-protein interaction disruptors, covalent and noncovalent PBP inhibitors, proteolysis-targeting chimeras (PROTACs), and cofactor-interface modulators. We also analyze the upstream kinase (MST1/2, LATS1/2) modulators, direct YAP/TAZ inhibitors and degraders, and emerging gene-, RNA-, antibody-, and cell-based therapies. We critically evaluate preclinical and early clinical performance across oncology, fibrosis, immunology, and regenerative medicine, distinguishing robust proof-of-concept from clinically meaningful benefit. We further dissect resistance mechanisms, on-target safety concerns, and the therapeutic-window limitations of pan-TEAD inhibition. Ultimately, we outline rational combination strategies, biomarker-guided patient selection, and future directions for paralog-selective and tissue-restricted Hippo-targeted therapeutics.