Epigenetic impacts of the acaricide flumethrin on honeybees (Apis mellifera).

Pkc53E mediates miR-316-dependent suppression of Yorkie-driven overgrowth.

RNF2 facilitates the progression of cervical cancer through the degradation of LATS1.

ROS-driven rewiring of Hippo-inflammation-polycomb axis by PFOA in 2D and 3D lung epithelial models.

The Multi-Faceted Landscape of TEAD Inhibition: a 2017-2025 Patent and Literature Review.

Corneal fibrosis, a major cause of corneal opacification and vision loss, is characterized by a progressive increase in extracellular matrix (ECM) stiffness. This heightened stiffness accelerates fibrosis, establishing a self-perpetuating vicious cycle. However, the central mechanotransduction mechanisms through which matrix stiffness drives fibrotic progression remain poorly understood. To investigate this, primary human corneal fibroblasts were cultured on hydrogels with varying stiffness. Label-free quantitative proteomics revealed that increased ECM stiffness triggered widespread proteomic reprogramming, with significant enrichment in pathways related to fibrosis, Hippo signaling, cytoskeletal remodeling, and glycolysis. Further experimental validation confirmed that matrix stiffness coordinately activated the Hippo pathway effectors YAP/TAZ (Yes-associated protein 1/Transcriptional coactivator with PDZ-binding motif) and the canonical Wnt component β-catenin. Importantly, in human fibrotic corneal tissues obtained from clinical specimens, YAP and β-catenin were highly expressed and spatially co-localized with the myofibroblast marker alpha-smooth muscle actin (α-SMA). Modulation of the YAP/TAZ-β-catenin axis through genetic silencing (siRNA) and pharmacological approaches, including pathway inhibitors and agonists, significantly altered stiffness-induced fibrotic phenotypes. Mechanistic studies revealed that YAP/TAZ functioned as key mechanotransducers upstream of β-catenin, and that YAP and β-catenin physically interacted. Collectively, this work identifies the YAP/TAZ-β-catenin pathway as one of the key mechanotransduction pathways of stiffness-induced corneal fibrosis. These findings not only deepen our understanding of the biomechanical mechanisms underlying fibrosis but also provide a mechanistic rationale for developing anti-fibrotic biomaterials and therapies that target mechanical sensing. STATEMENT OF SIGNIFICANCE: This study identifies the YAP/TAZ-β-catenin axis as one of the key mechanotransduction pathways in stiffness-driven corneal fibrosis. Label-free quantitative proteomics revealed widespread protein expression alterations in primary human corneal fibroblasts subjected to pathological matrix stiffness. Pharmacological and genetic perturbations confirmed that YAP/TAZ acts upstream of β-catenin to promote myofibroblast differentiation, supported by evidence of direct protein-protein interaction and co-localization of YAP and β-catenin in fibrotic human corneal tissue. These findings highlight the importance of the mechanical microenvironment in corneal fibrosis beyond classical biochemical stimuli and suggest that targeting this pathway may offer a therapeutic strategy for corneal fibrosis.

The Hippo signaling pathway represents a critical regulatory mechanism governing organ size control, tissue homeostasis, and tumor suppression through modulation of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). This review focuses on recent structural biology advances in understanding the molecular architecture and regulatory mechanisms of the Hippo pathway. We examine the core signaling complexes, mammalian sterile 20-like kinases 1 and 2 (MST1/2)-Salvador ortholog 1 (SAV1) and large tumor suppressor 1/2 (LATS1/2)-Mps One Binder (MOB1), revealing their intricate assembly mechanisms and activation dynamics. The review highlights the striatin-interacting phosphatase and kinase (STRIPAK) complex as a pivotal negative regulator through its unique PP2A-striatin core architecture. We further explore upstream regulatory proteins including NF2/Merlin and angiomotin family proteins, highlighting angiomotin-induced conformational changes and membrane-associated spatial organization that orchestrate pathway activation. Importantly, disease-associated mutations cluster at critical structural interfaces, providing mechanistic insights into pathological Hippo pathway dysregulation. These structural studies not only advance our fundamental understanding of signal transduction mechanisms but also provide a foundation for exploiting the Hippo pathway in regenerative medicine and cancer therapy.

The Hippo signaling pathway, first identified in Drosophila, is a conserved regulator of organ size and tissue homeostasis that balances proliferation and apoptosis. In mammals, its core kinases mammalian Sterile 20-like kinases 1 and 2 (MST1/2) and large tumor suppressor kinases 1 and 2 (LATS1/2) restrict the transcriptional coactivators Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), whose nuclear translocation drives cell proliferation and survival. In the intestine, YAP/TAZ activity is normally repressed to maintain homeostasis, but transient activation following injury promotes regeneration. Injury-induced YAP signaling triggers a regenerative transcriptional program marked by fetal gene re-expression and the emergence of Clusterin (Clu)-positive revival stem cells (revSCs), which restore leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) intestinal stem cells and epithelial integrity. Cross talk between Hippo, Wingless-related integration site (WNT), transforming growth factor β (TGF-β), and p53 signaling orchestrates this dynamic repair process, with precise temporal control of YAP essential for successful regeneration. Dysregulation of these interactions contributes to colorectal cancer tumorigenesis, highlighting the Hippo pathway as a central hub linking intestinal homeostasis, regeneration, and cancer.

Targeting the YAP-mediated stromal signaling unlocks chemoresistance in a human organoid fibrosis model.

Creatine metabolism regulates trophectoderm formation in early mouse embryos via an energy-cytoskeleton-YAP axis.

Melanoma, originating from the malignant change in skin melanocytes, is highly metastatic, yet effective treatments to prevent its spread are still lacking. Lysine-specific histone demethylase 1 (LSD1) functions as an epigenetic modifier; however, its role in melanoma remains incompletely elucidated. In this study, we determined that LSD1 expression is upregulated in metastatic melanoma relative to primary melanoma, which is indicative of a poor prognosis. Subsequent experiments revealed that targeting LSD1 effectively suppresses melanoma metastasis in both in vitro and in vivo models. Mechanistically, the pharmacological or genetic inhibition of LSD1 induces the phosphorylation and subsequent degradation of Yes-associated protein (YAP), a critical component of the Hippo signaling pathway that is strongly linked to tumor metastasis. Furthermore, ChIP-qPCR analysis indicates that the LSD1 inhibition enhances H3K4me2 modification at the promoter regions of NF2 and LATS1/2, thereby promoting their transcriptional activation. This results in increased expression of NF2 (encoded by NF2) and LATS1/2, ultimately activating the Hippo pathway. These findings not only enhance our understanding of the molecular mechanisms driving melanoma metastasis but also establish a novel theoretical basis for the development of LSD1 inhibitors and targeted therapeutic strategies for melanoma.

The mechanical traction caused by high cross-linking extracellular matrix (ECM) can promote the continuous activation of hepatic stellate cells (HSCs) by yes-associated protein (YAP)-mediated mechanical signal. Therefore, targeted inhibiting the activation of HSCs induced by mechanical traction is the main measure to improve liver fibrosis. The activated HSCs (aHSCs)-targeted drug delivery nanosystem of verteporfin@polyethyleneimine-vitamin A (VP@PSA), which loaded VP a small molecule inhibitor of YAP in the Hippo signaling pathway to regulate mechanical signal transduction was constructed. The particle size of VP@PSA was 167.1 ± 1.5 nm with great stability, and the drug loading of VP was 34.39 ± 2.41% and encapsulation efficiency was 93.28 ± 1.57%. The targeting and therapeutic effect of VP@PSA were verified by immunofluorescence, flow cytometry and competitive inhibition experiments. The biocompatibility was evaluated by hemolysis, pyrogen, vascular stimulation, respiration and behavior. Compared with non-targeted delivery system, VP@PSA showed best targeting ability to aHSCs among different kinds of liver cells. VP@PSA had an excellent therapeutic effect on suppressing the activation of HSCs, reducing ECM deposition and improving liver fibrosis by regulating YAP/ lysyl oxidase like 2/connective tissue growth factor signalin vitroandin vivo. Furthermore, VP@PSA had favorable biological safety and no toxicity to the main organs. The constructed VP@PSA delivery system laid a solid theoretical and experimental foundation for developing clinical targeted drugs for liver fibrosis.

Central kinases of the Hippo tumor suppressor pathway phosphorylate the transcriptional coactivators YAP and TAZ to sequester them in the cytoplasm. In cancer, Hippo pathway kinases have reduced activity, leading to translocation of YAP and TAZ into the nucleus, where they engage TEADs and other transcription factors. Here, we explore whether heterobifunctional small molecules that bind to the TEAD allosteric lipid-binding pocket can degrade the TEAD·YAP/TAZ complex. We design and synthesize heterobifunctional molecules that consist of flufenamic acid analogs that bind to the allosteric TEAD lipid pocket, a long and flexible linker, and thalidomide to engage E3 ubiquitin ligase component cereblon. Proteasomal degradation of TEAD, YAP, and TAZ for the carboxylic acid compounds was modest, but methyl ester analogs led to substantial degradation of these proteins in cancer cells. This work provides a strategy for depletion of YAP and TAZ and for exploration of their TEAD-dependent and TEAD-independent activities in vivo.

Interorgan communication has emerged as a fundamental mechanism for maintaining systemic homeostasis, and its disruption contributes to the development of metabolic diseases, chronic inflammation, and cancer. The Hippo signaling pathway, traditionally known for controlling organ size, has recently been redefined as a context-dependent coordinator of systemic cues. By translating hormonal, metabolic, and microbial signals into coordinated cellular responses, Hippo signaling serves as a bidirectional communication hub that not only interprets systemic inputs but also generates "outputs" that connect multiple organ systems. In this review, we summarize how Hippo signaling integrates diverse stimuli within key interorgan axes (e.g., gut-liver, gut-pancreas, and adipose-peripheral organs), and how organ-specific Hippo activity, particularly in adipose tissue and skeletal muscle, generates systemic outputs influencing metabolism. This integration occurs through context-specific mechanisms, allowing Hippo signaling to adapt cellular programs to physiological or pathological conditions. Despite recent progress, the mechanisms by which Hippo signaling prioritizes and integrates multiple systemic inputs and transmits its effects across organs remain incompletely understood. Elucidating these processes will be crucial to establishing Hippo signaling as a unifying framework of interorgan communication and understanding its broader implications in systemic physiology and disease.

In this study, a series of mechanically tunable CMOT hydrogels was successfully developed, which enable colon‑targeted delivery and controlled degradation via dynamic Schiff‑base cross‑linking. Among them, the moderately stiff CMOT‑M hydrogel best mimics the native mechanical microenvironment of intestinal tissue, significantly alleviating DSS‑induced colitis symptoms, restoring the expression of tight‑junction proteins (ZO‑1, occludin), and suppressing excessive production of inflammatory cytokines (TNF‑α, IL‑6, IL‑1β). Mechanistic investigations revealed that the CMOT‑M hydrogel modulates the Hippo signaling pathway through integrin‑cytoskeletal tension transmission, thereby precisely tuning the phosphorylation status and nuclear translocation of YAP/TAZ: during the acute phase, it moderately activates YAP/TAZ to promote epithelial proliferation and migration; during the repair phase, it suppresses excessive YAP/TAZ activation, guiding stem‑cell differentiation and preventing fibrosis. After loading with the herbal formula QCXPY (CMOT@QCXPY), the hydrogel further synergistically inhibits the IL‑6/STAT3 pathway and reshapes the gut microbiota, establishing a multidimensional regulatory network integrating mechanical, immune, and microbial cues. This work demonstrates that material stiffness serves as a critical design parameter that can promote mucosal regeneration through YAP‑mediated mechanosensing, offering a novel mechano‑therapeutic strategy for ulcerative colitis.

Cancer arises from oncogenic clones, yet the dynamic mechanisms driving their stepwise evolution toward malignancy remain incompletely understood. Here, we establish the Atlas of Ras-driven Tumors in Drosophila (ART-D), a systematic, cross-species platform that dissects the molecular and phenotypic trajectories of tumorigenesis across ten genetically defined RasV12-driven models. By integrating longitudinal phenotypic profiling, we define three conserved stages of tumor development-initiation, promotion, and progression-distinguished by distinct shifts in tumor burden and tumor-induced cachexia. Transcriptomic analysis reveals stage-specific signaling rewiring: early tumorigenesis is characterized by co-activation of JAK/STAT, NF-κB/Toll, and MAPK pathways, whereas malignant progression is driven by Notch hyperactivation and Hippo pathway inactivation. Through integrative multi-omics and machine learning, we uncover an evolutionarily conserved pathogenic network coordinating JNK, NF-κB/Toll, Notch, and Hippo signaling, which we functionally validate across species. ART-D serves as a transformative resource bridging Drosophila genetics and human cancer biology, offering a robust framework for decoding conserved oncogenic principles and identifying of stage-specific vulnerabilities in RAS-driven cancers.

The Ion Channel, CFTR, assembles with HIPPO pathway proteins TAZ and YAP in polycystic kidney disease.

Combination of alantolactone and temozolomide targets stemness and lipid metabolism in glioblastoma through YAP1-Hippo signaling.

The organization of the cell's cytoskeletal filaments is coordinated through a complex network of signaling cascades activated by both internal and external cues. Two major actin regulatory pathways are signal transduction through Rho family GTPases and growth and proliferation signaling through the Hippo pathway. These two pathways define the actin cytoskeleton, controlling foundational cellular attributes such as morphology, the organization of actin-based structures, and are hijacked to promote proliferation and motility in aggressive cancers. In this study, we use human epithelial cells to investigate the interplay between the Hippo and Rho Family signaling pathways. We identify that the RhoA GTPase-activating protein, ARHGAP18, forms a complex with two Hippo pathway components, the tumor suppressor Merlin (NF2), and the transcriptional coactivator YAP. Using super resolution STORM microscopy, we characterize single-filament-level changes in the actin cytoskeleton that arise from CRISPR/CAS9 knockout of ARHGAP18. We report that the loss of ARHGAP18 results in cytoskeletal alterations associated with dysregulation of RhoA signaling at apical structures and aberrant nuclear localization of YAP. These findings provide additional support for models suggesting that Hippo and Rho family GTPase signaling cascades may be temporally and spatially coordinated in the regulation of the actin cytoskeleton.

Postmenopausal osteoporosis (PMOP) is a skeletal disorder marked by progressive bone mineral density decline and increased susceptibility to fractures. Accumulating evidence indicates that coupled osteogenesis and angiogenesis are indispensable for bone remodeling and repair. This study investigated the therapeutic potential of dendrobine in concurrently modulating osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and angiogenic activity in the context of PMOP. BMSCs were isolated from Sprague-Dawley rats and rigorously characterized prior to experimentation. Cell viability was quantified using CCK-8 assays, and apoptosis was assessed via flow cytometry. To evaluate angiogenesis, tube formation capacity was measured following coculture of BMSCs and human umbilical vein endothelial cells (HUVECs), and protein levels of angiogenic factors (VEGF, MMP2, and MMP9) were quantified by western blotting. Osteogenic differentiation was assessed by Alizarin red staining for mineralized nodule formation, ALP staining, and western blotting of osteogenic markers (Runx2, OCN, and OPN). Following PMOP modeling via bilateral ovariectomy (OVX), H&E staining and micro-computed tomography were conducted. Western blotting was performed to measure protein levels of core Hippo pathway components (Mst1, Lats1, Yap1, and Taz) in femoral bone tissue. Results showed that dendrobine significantly promoted BMSC viability and suppressed apoptosis in a dose-dependent manner. In BMSC-HUVEC cocultures, dendrobine markedly augmented tube formation and upregulated VEGF, MMP2, and MMP9. Concurrently, dendrobine enhanced osteogenic differentiation, as evidenced by increased ALP activity, enhanced mineralization, and elevated protein levels of Runx2, OCN, and OPN. In OVX rats, dendrobine treatment ameliorated trabecular bone loss and restored bone parameters toward sham levels. Consistently, dendrobine elevated the expression of osteogenic and angiogenic proteins in vivo. Moreover, dendrobine suppressed Mst1 and Lats1 expression while promoting Yap1 and Taz expression in OVX rats. In conclusion, dendrobine alleviates PMOP by coordinately enhancing osteogenesis and angiogenesis through inhibition of the Hippo pathway and subsequent activation of the Yap1/Taz signaling.