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Open research questions in Hippo pathway signaling and YAP/TAZ

27 unresolved questions extracted from the limitations and future-work sections of 101 Hippo pathway signaling and YAP/TAZ papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The mammary gland is a composite organ whose architec- ture and function depend on dynamic crosstalk between epithelial and adipose compartments. Mammary adipose tissue should no longer be viewed as a passive volume-fill- ing compartment. Instead, it is a dynamic stromal regula- tor that shapes mammary development, adult homeostasis, reproductive remodeling, and disease susceptibility through endocrine and paracrine signaling, matrix organization, immune interactions, and metabolic exchange. A central conclusion of this review is that mammary adipocyte plas- ticity is not a single phenomenon but a layered spectrum of fate-related, phenotypic, and metabolic changes whose interpretation depends on developmental context and evi- dentiary strength. The key unresolved questions are now more sharply defined: how to distinguish true fate transitions from delipi- dation; how to separate mature-adipocyte plasticity from stromal-progenitor behavior; how endocrine, immune, and mechanical signals are integrated across developmen- tal stages; and which murine mechanisms are truly con- served in the human breast. Answering these questions will require lineage-resolved genetic models, spatially resolved single-cell approaches, and careful cross-species analysis. These are precisely the tools needed to move mammary adipose biology from an interesting stromal backdrop to a mechanistically central component of breast biology and disease. Author contributions Y.L. conceived the article. P.C. performed the literature search and wrote the first draft of the manuscript. J.C. and Y.L. critically revised the manuscript for important intellectual con- tent. All authors contributed to manuscript revision and approved the final version. Funding This work was supported by the National Natural Science Foundation of China (81901976, 82472585, 82372544), Guang- dong Provincial Natural Science Foundation (2023A1515011741), Guangzhou Science and Technology Program (2023A04J2348), Nanfang Hospital’s Outstanding Young Talent Cultivation Program (K50906009, K50304020), Nanfang Hospital’s Scientific Research Development Fund(K51701101). Data availability No datasets were generated or analysed during the current study.

    Mammary adipocyte plasticity and epithelial crosstalk: roles in development, remodeling, and disease · 2026 · DOI

  • ABSTRACT Epithelial‐mesenchymal transition (EMT) is a key driver of breast cancer progression, yet the upstream transcriptional and ubiquitin‐mediated mechanisms that modulate Hippo signaling remain incompletely defined.

    ZBTB11 Promotes Breast Cancer Progression by Activating FBXO28‐Mediated MST1 Degradation and Suppressing Hippo Signaling · 2026 · DOI

  • Recent genomic, single-cell sequencing, and spatial transcriptomics studies converge on a central conclusion: gastric cancer cannot be fully described by a set of static subtypes. Instead, tumors move through a landscape of epithelial lineages and stromal reprogramming shaped by inflammation, mechanics, and therapy. Framing YAP/TAZ as coordinators of epithelial-stromal plasticity connects genotype, histology, and microenvironmental architecture, motivating new classification and treatment paradigms. Priorities include mapping YAP/TAZ activity and ecotypes in large, clinically annotated cohorts; defining how events such as CDH1 loss and RHOA pathway alterations rewire Hippo dependence; and developing preclinical models that preserve tumor-stroma coupling to evaluate how Hippo-targeted interventions reshape heterogeneity and plasticity [43,49,58]. Ultimately, clinically useful frameworks will need to combine stable molecular strata with dynamic ecotype readouts, enabling therapies that not only match baseline subtype but also anticipate and prevent transitions into drug-tolerant, metastatic states [34,46]. Such approaches could illuminate new means to manage the devastating disease of advanced gastric cancer.

    Hippo-YAP/TAZ signaling in gastric cancer: orchestrating epithelial-stromal heterogeneity, plasticity, and therapy resistance · 2026 · DOI

  • To date, there are limited data that detail the constituents and regulatory functions of the Hippo pathway in YAP-negative tumors like NEPC.

    Systematic analysis of hippo pathway signaling identifies TEAD1 as a transcriptional regulator of neuroendocrine prostate cancer · 2026 · DOI

  • Abstract Hydrogen peroxide (H 2 O 2 ) is a crucial signaling molecule in vertebrate regeneration, yet its functional role across diverse lizard species remains incompletely defined.

    Reactive oxygen species drive wound epithelium and blastema formation in regenerating tail of Scincella tsinlingensis · 2026 · DOI

  • The developmental program governing meibomian gland (MG) morphogenesis and proliferation remains poorly understood, largely due to the lack of physiologically relevant model systems.

    Modeling Meibomian Gland Development and Dysfunction: A Mouse-Derived Organoid System Reveals Hippo-YAP as a Critical Regulator · 2026 · DOI

  • Abstract Control of organ size during development and homeostasis relies on balanced regulation of Hippo pathway transcriptional output, yet how TEAD activity is precisely regulated in vivo remains unclear.

    Two distinct modes of Vgll4-mediated Tead regulation control organ size in zebrafish · 2026 · DOI

  • Several limitations should be considered when interpret- ing the links between YAP/TAZ signaling and osteoporosis, osteoarthritis. First, mechanistic evidence is still dominated by animal and in vitro studies, whereas human data remain limited and often correlative (e.g., expression, localization) with potential confounders (age, comorbidities, treatments, disease stage). Second, faithfully modeling physiologic versus pathologic loading is challenging; common unload- ing, loading paradigms and 2D stiffness, flow systems only approximate the native lacunar–canalicular and osteochon- dral mechanical niches, so extrapolation to human disease should be regarded as hypothesis-generating. Third, YAP and TAZ exhibit cell-type- and stage-dependent, sometimes divergent roles across osteocytes, osteoblast-lineage cells, osteoclast precursors, and joint tissues. Finally, YAP/TAZ can be controlled by both Hippo-dependent and Hippo- independent inputs (adhesion–cytoskeleton tension, inte- grin–FAK, RhoA, ROCK, ion, energy-sensing pathways), complicating causal attribution. Future lineage-resolved in vivo studies under controlled loading and better human datasets are needed to strengthen translational inference.

    Role of YAP/TAZ Mechanobiological Signaling in Osteoporosis and Osteoarthritis · 2026 · DOI

  • The limited number of studies directly investigating the functional role of the Hippo signaling pathway in pediatric gliomas makes it difficult to draw definitive conclusions. Furthermore, the wide heterogeneity of pediatric glioma subtypes, together with the historical differences in tumor classification among older studies, complicates the inter- pretation and comparison of findings, particularly those related to YAP/TAZ signaling. Although this review incor- porates substantial evidence from single-cell transcriptomic and genomic studies, it is a narrative review rather than a formal meta-analysis and thus, a selection bias cannot be fully excluded. Finally, the rarity of several pediatric glioma 40 Page 16 of 23 Cancer and Metastasis Reviews (2026) 45:40 subtypes reduces the reproducibility and statistical power of individual studies, limiting the ability to derive broadly generalizable conclusions.

    The Hippo signaling pathway in pediatric brain tumors: molecular mechanisms and therapeutic opportunities · 2026 · DOI

  • Collectively, current evidence positions the Hippo pathway as a central and context-sensitive regulator of antiviral immu- nity, viral replication, and tissue remodelling. Rather than operating as a simple on-off switch, Hippo signalling integrates host defence mechanisms with viral countermeasures at multiple regulatory levels. Future studies should prioritise tempo- ral and cell-type-specific analyses, clarify non-canonical Hippo signalling in immunity, and define how viral proteins selec- tively rewire YAP/TEAD transcriptional program. A deeper mechanistic understanding will be essential for safely exploiting Hippo-YAP signalling as a therapeutic target in viral disease, chronic inflammation, and virus-triggered autoimmunity.

    Hippo signalling as a nexus in host–virus interactions · 2026 · DOI

  • which was a valid alternative method to explore the impact of YAP1 on immunotherapy. The impact of genetic ablation of YAP1 on immunotherapy response in ESCC remains to be elucidated and warrants further investigation in future studies.

    Proteome profiles of esophageal squamous cell carcinoma tie mitochondrial complex I to immunotherapy · 2026 · DOI

  • In conclusion, GPCRs are involved in each stage of the wound healing process with distinct roles and perform different functions. They play an important role in the regulation of immune responses in the inflammatory phase and cell proliferation and differentiation in the tissue regeneration phase during damage repair. Cutaneous wound repair and regeneration are mainly related to dermal Investigation, Writing – HC: Conceptualization, Writing – original draft, Visualization, Funding acquisition. KZ: Conceptualization, Writing – original review and editing, draft, Visualization. YX: Writing – Investigation. XF: Investigation, Writing – review and editing. CZ: editing. TZ: Writing – review and editing, Investigation. FL: Writing – review and editing, Supervision. HC: Writing – review and editing, Supervision. HZ: Writing – review and editing, Supervision. CD: Supervision, Writing – review and editing. WL: Supervision, Writing – review and editing. review and Frontiers in Cell and Developmental Biology 11 frontiersin.org Chen et al.

    GPCRs as key regulators in wound healing · 2026 · DOI

  • We discovered that expression of PDEF is decreased during prostate cancer progression and re-expression of PDEF limits prostate cancer metastasis in part by promoting luminal epithelial phenotype, but mechanisms of PDEF action are not completely understood.

    Abstract 1457: PDEF restricts prostate cancer cellular plasticity in part by modulating YAP1/TAZ-TEAD transcriptional network · 2023 · DOI

  • We observed robust activation of the Smad and Hippo pathways; however, the precise mechanistic regulatory hierarchy and po- tential interplay between these two crucial signaling cascades in response to rhBMP-2 remain unclear.

    Recombinant bone morphogenetic protein-2 attenuates colorectal cancer progression by orchestrating Hippo pathway activation, Yes-associated protein inhibition, and epithelial–mesenchymal transition suppression · 2026 · DOI

  • YAP also functionally interacts with the Wnt/β-catenin pathway, yet how polarity cues coordinate this pathway crosstalk remains poorly understood.

    Homer condensates orchestrate YAP–Wnt signaling crosstalk downstream of the Crumbs polarity complex · 2026 · DOI

  • However, the feedback mechanisms in stem cells that prevent hyperproliferation remain unclear, and their dysregulation can lead to organ failure and cancer.

    Homeostatic control of stem cell activity during intestinal regeneration. · 2026 · DOI

  • Src-family kinases (SFKs) regulate proliferation in colonic epithelial cells (CECs), but the mechanisms that restrain their activity remain poorly defined.

    Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis · 2026 · DOI

  • ABSTRACT Retinal angiogenesis relies on a precisely timed interaction between astrocytes and endothelial cells (ECs), yet the transcriptional regulatory program underlying this complex neurovascular crosstalk remains poorly characterized.

    Zeb2 Controls Retinal Physiological and Pathological Angiogenesis by Regulating Astrocyte Proliferation and Differentiation · 2026 · DOI

  • Lysine-specific histone demethylase 1 (LSD1) functions as an epigenetic modifier; however, its role in melanoma remains incompletely elucidated.

    Targeting lysine-specific demethylase 1 inhibits melanoma metastasis via the NF2-Hippo-YAP pathway · 2026 · DOI

  • A key open question is whether a single snapshot of signaling is sufficient to predict cell fate, especially given substantial evidence that signaling dynamics shape fate decisions.

    Interpretable decoding of cell fate from a snapshot of combinatorial signaling · 2026 · DOI

  • it in genetic resolution, Despite providing systematic insights into Ras-driven tumorigenesis, several limitations warrant acknowledgment.

    Cross-species insights from ART-D to uncover evolutionarily conserved oncogenic mechanisms · 2026 · DOI

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27 open questions have been extracted from the limitations and future-work passages of 101 Hippo pathway signaling and YAP/TAZ papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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