Hippo-YAP/TAZ Signaling in Hematological Malignancies: Molecular Mechanisms, Pathway Crosstalk and Therapeutic Potential

Abstract

Abstract The Hippo signaling pathway represents an evolutionarily conserved regulatory network. It plays a central role in controlling cell proliferation, apoptosis, differentiation, and tissue homeostasis. Increasing evidence indicates that dysregulation of this pathway promotes the development and progression of hematological malignancies. This includes leukemia, lymphoma, and multiple myeloma. Notably, aberrant activation of downstream effectors—Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ)—plays a central role in this process. Abnormal YAP/TAZ signaling promotes malignant cell survival, proliferation, therapeutic resistance, and disease aggressiveness through extensive crosstalk with multiple oncogenic pathways, such as Phosphatidylinositol 3-kinase (PI3K)/ Protein kinase B (AKT), Transforming growth factor-beta (TGF-β), Wnt/β-catenin, and metabolic signaling networks. Notably, the biological functions of YAP/TAZ appear to be highly context-dependent, with both oncogenic and tumor-suppressive roles reported in different hematopoietic lineages and tumor microenvironments. In this review, we summarize the molecular architecture and regulatory mechanisms of the Hippo pathway, discuss its dysregulation and functional significance in major hematological malignancies, and highlight recent advances in Hippo-targeted therapeutic strategies, including YAP/TEA domain transcription factor (TEAD) inhibitors, upstream pathway modulators, and combination treatment approaches. We further outline current challenges and future opportunities for translating Hippo-based precision therapies into clinical practice. Despite promising preclinical findings, hematological malignancy-specific clinical evidence remains limited. Future studies are required to validate Hippo-targeted therapeutic strategies and establish clinically actionable biomarkers. A deeper understanding of Hippo signaling may provide novel insights into disease biology and accelerate the development of precision medicine approaches for hematological malignancies.