Yoda1 has been recognized as an effective pharmacological intervention for the treatment of critical bone defects. However, the local delivery strategy of Yoda1 is uncommon, and the underlying mechanism through which Yoda1 enhances osteogenesis has been poorly investigated. Here, we propose utilizing electrohydrodynamic (EHD)-printed microfibrous scaffolds as a drug carrier for loading Yoda1 through a polydopamine (PDA) coating, and the synthetic mechanisms for enhancing bone regeneration are explored. Yoda1 was successfully loaded on the surface of the EHD-printed microfibrous scaffolds with the assistance of PDA. The results of in vitro experiments demonstrated that the Yoda1-loaded microfibrous scaffold group exhibited a more than 2-fold increase in COL-I protein levels compared to the control group. Additionally, the expression levels of osteogenic indicators such as ALP, Runx2, and OCN genes were significantly increased by 2-4-fold compared to those in the control group. We revealed that Yoda1 can effectively activate the Piezo1-F-actin pathway, thereby facilitating YAP nucleation and promoting lysine histone acetylation. Consequently, this mechanism enhanced the functionality of YAP nucleation and upregulated the expression of COL-I. Moreover, when implanted in vivo, the Yoda1-loaded microfibrous scaffold group could promote macrophage M2 polarization, thereby enhancing bone regeneration at defect sites. It is believed that the localized release of Yoda1 via EHD-printed PCL scaffolds might represent a promising strategy for the clinically precise treatment of bone defects.

Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP's role in HCC progression, but the mechanisms are unclear. This study aims to clarify YAP's function in HCC, emphasizing its regulation of key pathways and targets.

Gene knockout and overexpression models were established in nude mice and cell lines of HCC cells to investigate YAP's impact on tumorigenesis. Additionally, functional assays and molecular biology techniques were employed to identify YAP's regulatory networks. The study demonstrates that LDHA-regulated lactate production promotes YAP activation and malignant phenotypes in HCC. Overexpression of LDHA in HepG2 and Huh7 cells increased lactate levels and activated the YAP pathway, enhancing cell proliferation, migration, and invasion. Lactate treatment also promoted these malignant phenotypes by inhibiting YAP phosphorylation at Ser127. In a xenograft model, lactate accelerated tumor growth through YAP activation. YAP lactylation at K102 antagonized its Ser127 phosphorylation, further promoting malignant progression.

This study highlights the significance of YAP in HCC pathogenesis, providing insights into potential therapeutic targets for HCC management.

Disulfidptosis is an emerging type of programmed cell death related to ROS accumulation and aberrant disulfide bond formation. Multiple myeloma (MM) is the second most prevalent hematologic malignancy characterized by a high synthesis rate of disulfide bond-rich proteins and chronic oxidative stress. However, the relationship between disulfidptosis and MM is still unclear.

Using the non-negative matrix factorization and lasso algorithm, we constructed the disulfidptosis-associated subtypes and the prognostic model on the GEO dataset. We further explored genetic mutation mapping, protein-protein interactions, functional enrichment, drug sensitivity, drug prediction, and immune infiltration analysis among subtypes and risk subgroups. To improve the clinical benefits, we combined risk scores and clinical metrics to build a nomogram. Finally, in vitro experiments examined the expression patterns of disulfidptosis-related genes (DRGs) in MM.

By cluster analysis, we obtained three subtypes with C2 having a worse prognosis than C3. Consistently, C2 exhibited significantly lower sensitivity to doxorubicin and lenalidomide, as well as a higher propensity for T-cell depletion and a non-responsive state to immunotherapy. Similarly, in the subsequent prognostic model, the high-scoring group had a worse prognosis and a higher probability of T-cell dysfunction, immunotherapy resistance, and cancer cell self-renewal. DRGs and risk genes were widely mutated in cancers. Subtypes and risk subgroups differed in ROS metabolism and the p53 signaling pathway. We further identified eight genes differentially expressed in risk subgroups as drug targets against MM. Then 27 drugs targeting the high-risk group were predicted. Based on the DRGs and risk genes, we constructed the miRNA and TF regulatory networks. The nomogram of combined ISS, age, and risk score showed good predictive performance. qRT-PCR of cell lines and clinical specimens provided further support for prognostic modeling.

Our research reveals the prognostic value of disulfidptosis in MM and provides new perspectives for identifying heterogeneity and therapeutic targets.

The most notable progress in renal clear cell carcinoma (ccRCC) in the past decades is the introduction of drugs targeting the VHL-HIF signaling pathway-associated angiogenesis. However, mechanisms underlying the development of VHL mutation-independent ccRCC are unclear. Here we provide evidence that the disrupted Hippo-YAP signaling contributes to the development of ccRCC independent of VHL alteration. We found that YAP1 and its primary target genes are frequently upregulated in ccRCC and the upregulation of these genes is associated with unfavorable patient outcomes. Research results derived from our in vitro and in vivo experimental models demonstrated that, under normoxic conditions, hyperactivated YAP1 drives the expression of FGFs to stimulate the proliferation of tumor and tumor-associated endothelial cells in an autocrine/paracrine manner. When rapidly growing cancer cells create a hypoxic environment, hyperactivated YAP1 in cancer cells induces the production of VEGF, which promotes the angiogenesis of tumor-associated endothelial cells, leading to improved tumor microenvironment and continuous tumor growth. Our study indicates that hyperactivated YAP1 is essential for maintaining ccRCC progression, and targeting the dual role of hyperactivated YAP1 represents a novel strategy to improve renal carcinoma therapy.

The nuclear pore complex (NPC), a channel within the nuclear envelope filled with intrinsically disordered proteins, regulates the transport of macromolecules between the nucleus and the cytoplasm. Recent studies have highlighted the NPC's ability to adjust its diameter in response to the membrane tension, underscoring the importance of exploring how variations in pore size influence molecular transport through the NPC. In this study, we investigated the relationship between pore size and transport rate and proposed a mathematical model describing this connection. We began by theoretically analyzing how the pore size scales with the characteristic dimensions of the mesh-like structure within the pore. By introducing key assumptions about how the meshwork structure influences molecular diffusion, we derived a mathematical expression for the transport rate based on the size of the pore and the transported molecules. To validate our model, we conducted Brownian dynamics simulations using a coarse-grained representation of the NPC. These simulations, performed across a range of pore sizes, demonstrated strong agreement with our model's predictions, confirming its accuracy and applicability. Our model is specifically tailored for small-to-medium-sized molecules, approximately 5 nanometers in size, making it relevant to a wide range of transcription factors and signaling molecules. It also extends to molecules with weak and transient interactions with FG-Nups, such as importin-β. By presenting this model formula, our study offers a quantitative framework for analyzing the effects of pore dilation on nucleocytoplasmic transport.

Despite advances in non-small cell lung cancer (NSCLC) therapies, resistance remains a major challenge. Ferroptosis, a form of regulated cell death, plays a key role in cancer progression and treatment response. However, the mechanisms governing ferroptosis in NSCLC are not fully understood. The Hippo pathway, which regulates cell proliferation, has recently been implicated in ferroptosis regulation. In this study, we identify Mitotic Spindle Positioning (MISP) as a critical inhibitor of ferroptosis in NSCLC. MISP is upregulated in NSCLC tissues, and its loss sensitizes cells to ferroptosis, reducing cell proliferation in vitro and in vivo. Mechanistically, MISP binds to the SARAH domain of MST1/2 kinases, inhibiting their homodimerization and autophosphorylation, leading to sustained activation of YAP, a transcriptional coactivator in the Hippo pathway. YAP activation increases SLC7A11 expression, which protects cells from ferroptosis. We also identify a mutant MISP-R390/391A that disrupts MISP-MST1/2 binding, further illustrating the MST1/2-dependent inhibition of Hippo signaling. Notably, MISP is a target of YAP, creating a feedback loop that amplifies YAP signaling. Our findings suggest a novel MISP-YAP axis regulating ferroptosis, positioning MISP as a potential therapeutic target for NSCLC, especially in cases with dysregulated YAP.

Large-scale cancer genetic/genomic studies demonstrated that papillary renal cell carcinoma (pRCC) is featured with a frequent shallow deletion of the upstream tumor suppressors of the Hippo/YAP signaling pathway, suggesting that this signaling pathway may play a role in pRCC development. Here we develop a transgenic mouse model with a renal epithelial cell-specific hyperactivation of YAP1 and find that hyperactivation of YAP1 can induce dedifferentiation and transformation of renal tubular epithelial cells leading to the development of pRCC. We analyze at the single-cell resolution the cellular landscape alterations during cancer initiation and progression. Our data indicate that the hyperactivated YAP1, via manipulating multiple signaling pathways, induces epithelial cell transformation, MDSC (Myeloid-derived suppressor cells) accumulation, and pRCC development. Interestingly, we find that depletion of MDSC blocks YAP1-induced kidney overgrowth and tumorigenesis. Inhibiting YAP1 activity with MGH-CP1, a recently developed TEAD inhibitor, impedes MDSC accumulation and suppresses tumor development. Our results identify the disrupted Hippo/YAP signaling as a major contributor to pRCC and suggest that targeting the disrupted Hippo pathway represents a plausible strategy to prevent and treat pRCC.

Long-term peritoneal dialysis (PD) leads to peritoneal damage and chronic inflammation, resulting in peritoneal fibrosis (PF). Emerging evidence suggests that yes-associated protein (YAP) is a key player in fibrogenesis across various organs. However, its role in PD-induced PF remains unclear. We used NIH/3T3 cells, primary mouse fibroblasts, and conditional YAP knockout (CKO) mice with glioma-associated oncogene 1 (Gli1)-specific YAP deletion. The effects of YAP knockdown and verteporfin, a YAP inhibitor, on fibroblast-to-mesenchymal transition (FMT) and angiogenesis were evaluated. Transforming growth factor-beta (TGF-β) induced YAP expression and promoted fibroblast-to-myofibroblast transition (FMT) in 3T3 fibroblasts, upregulating collagen 1A1, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF). YAP knockdown and verteporfin treatment reduced these FMT markers and inhibited smad2/3 phosphorylation. In vivo, YAP and Gli1-expressing cells were upregulated in PD-induced PF. Conditional YAP knockout in Gli1+ cells and verteporfin treatment significantly reduced fibrosis and α-SMA, collagen 1, TGF-β, CTGF, and phosphorylated smad2/3 expression in the peritoneum and peritoneal angiogenesis. YAP plays a pivotal role in FMT during PD-induced PF. Conditional YAP deletion in Gli1-expressing cells and verteporfin treatment represent promising antifibrotic strategies for long-term PD patients.

Although blue light has been known to negatively affect skin cells, its detailed signaling mechanisms and anti-blue light agents have not been clearly elucidated. We investigated the involvement of Yes-associated protein (YAP)-mediated Hippo signaling in blue light-induced apoptosis, depending on the degree of blue light exposure. Additionally, we elucidated the effects of melatonin on blue light-irradiated keratinocytes and examined their action mechanisms. After blue light irradiation, its effects and antagonizing effects of melatonin on cell proliferation, apoptosis, DNA damage, and transient receptor potential vanilloid 1 (TRPV1)/YAP-mediated signaling were examined in HaCaT cells using western blots, image analysis, flow cytometric analysis, co-immunoprecipitation, and immunocytochemistry. We found that melatonin treatment attenuated the reduced cell viability and increased production of reactive oxygen species (ROS) in response to blue light irradiation. In the experiments to investigate the mechanism of action of blue light and melatonin, we found that YAP changed its binding protein, either p73 or TEAD, depending on the degree of blue light exposure. Melatonin treatment reduced blue light-induced phosphorylation of TRPV1 and MST1/2. Upon treatment with capsazepine, an antagonist of TRPV1, MST1/2 activation also reduced. Furthermore, we found that prolonged blue light irradiation induced DNA damage, which in turn induced YAP-p73 nuclear translocation. These effects were also notably attenuated by melatonin. These findings indicate that depending on the duration of blue light irradiation, two different YAP-mediated Hippo signaling pathways are activated. Additionally, these findings suggest that melatonin could be a potential therapeutic agent for blue light-induced skin damage.

The skeletal system comprises closely related yet functionally distinct bone and cartilage tissues, regulated by a complex network of transcriptional factors and signaling molecules. Among these, core-binding factor subunit beta (Cbfβ) emerges as a critical co-transcriptional factor that stabilizes Runx proteins, playing indispensable roles in skeletal development and homeostasis. Emerging evidence from genetic mouse models has highlighted the essential role of Cbfβ in directing the lineage commitment of mesenchymal stem cells (MSCs) and their differentiation into osteoblasts and chondrocytes. Notably, Cbfβ deficiency is strongly associated with severe skeletal dysplasia, affecting both endochondral and intramembranous ossification during embryonic and postnatal development. In this review, we synthesize recent advancements in understanding the structural and molecular functions of Cbfβ, with a particular focus on its interactions with key signaling pathways, including BMP/TGF-β, Wnt/β-catenin, Hippo/YAP, and IHH/PTHrP. These pathways converge on the Cbfβ/RUNX2 complex, which orchestrates a gene expression program essential for osteogenesis, bone formation, and cartilage development. The integration of these signaling networks ensures the precise regulation of skeletal development, remodeling, and repair. Furthermore, the successful local delivery of Cbfβ to address bone abnormalities underscores its potential as a novel therapeutic target for skeletal disorders such as cleidocranial dysplasia, osteoarthritis, and bone metastases. By elucidating the molecular mechanisms underlying Cbfβ function and its interactions with key signaling pathways, these insights not only advance our understanding of skeletal biology but also offer promising avenues for clinical intervention, ultimately improving outcomes for patients with skeletal disorders.

The Hippo signaling pathway is a pivotal regulator of tissue homeostasis, organ size, and cell proliferation. Its dysregulation is profoundly implicated in various forms of cancer, making it a highly promising target for therapeutic intervention. This review extensively evaluates the mechanisms underlying the dysregulation of the Hippo pathway in cancer cells and the molecular processes linking these alterations to tumorigenesis. Under normal physiological conditions, the Hippo pathway is a guardian, ensuring controlled cellular proliferation and programmed cell death. However, numerous mutations and epigenetic modifications can disrupt this equilibrium in cancer cells, leading to unchecked cell proliferation, enhanced survival, and metastatic capabilities. The pathway's interaction with other critical signaling networks, including Wnt/β-catenin, PI3K/Akt, TGF-β/SMAD, and EGFR pathways, further amplifies its oncogenic potential. Central to these disruptions is the activation of YAP and TAZ transcriptional coactivators, which drive the expression of genes that promote oncogenesis. This review delves into the molecular mechanisms responsible for the dysregulation of the Hippo pathway in cancer, elucidating how these disruptions contribute to tumorigenesis. We also explore potential therapeutic strategies, including inhibitors targeting YAP/TAZ activity and modulators of upstream signaling components. Despite significant advancements in understanding the Hippo pathway's role in cancer, numerous questions remain unresolved. Continued research is imperative to unravel the complex interactions within this pathway and to develop innovative and effective therapies for clinical application. In conclusion, the comprehensive understanding of the Hippo pathway's regulatory mechanisms offers significant potential for advancing cancer therapies, regenerative medicine, and treatments for chronic diseases. The translation of these insights into clinical practice will necessitate collaborative efforts from researchers, clinicians, and pharmaceutical developers to bring novel and effective therapies to patients, ultimately improving clinical outcomes and advancing the field of oncology.

Loss of pancreatic islet cell mass and function is one of the most important factors in the development of type 2 diabetes mellitus, and hyperglycemia-induced lesions in other organs are also associated with apoptosis or hyperproliferation of the corresponding tissue cells. The Hippo signaling pathway is a key signal in the regulation of cell growth, proliferation and apoptosis, which has been shown to play an important role in the regulation of diabetes mellitus and its complications. Excessive activation of the Hippo signaling pathway under high glucose conditions triggered apoptosis and decreased insulin secretion in pancreatic islet cells, while dysregulation of the Hippo signaling pathway in the cells of other organ tissues led to proliferation or apoptosis and promoted tissue fibrosis, which aggravated the progression of diabetes mellitus and its complications. This article reviews the mechanisms of Hippo signaling, its individual and reciprocal regulation in diabetic pancreatic pathology, and its emerging role in the pathophysiology of diabetic complications. Potential therapeutics for diabetes mellitus that have been shown to target the Hippo signaling pathway are also summarized to provide information for the clinical management of type 2 diabetes mellitus.

Gastric cancer (GC) ranks fourth in global mortality rates and fifth in prevalence, making it one of the most common cancers worldwide. Recent clinical studies have highlighted the potential of immunotherapies as a promising approach to treating GC. This study aims to shed light on the most impactful therapeutic strategies in the context of GC immunotherapy, highlighting both established and emerging approaches.

This review examines over 160 clinical studies conducted globally, focusing on the effectiveness of various immunotherapy modalities, including cancer vaccines, adoptive cell therapy, immune checkpoint inhibitors (ICIs), and monoclonal antibodies (mAbs). A comprehensive search of peer-reviewed literature was performed using databases such as Web of Science, PubMed, and Scopus. The selection criteria included peer-reviewed articles published primarily within the last 10 years, with a focus on studies that provided insights into targeted therapies and their mechanisms of action, clinical efficacy, and safety profiles. The findings indicate that these immunotherapy strategies can enhance treatment outcomes for GC, aligning with current treatment guidelines. ICIs like pembrolizumab and nivolumab have shown significant survival benefits in specific GC subgroups. Cancer vaccines and CAR-T cell therapies demonstrate potential, while mAbs targeting HER2 and VEGFR pathways enhance outcomes in combination regimens. We discuss the latest advancements and challenges in targeted therapy and immunotherapy for GC. Given the evolving nature of this field, this research emphasizes significant evidence-based therapies and those currently under evaluation rather than providing an exhaustive overview. Challenges include resistance mechanisms, immunosuppressive tumor environments, and inconsistent results from combination therapies. Biomarker-driven approaches and further research into emerging modalities like CAR-T cells and cancer vaccines are critical for optimizing treatments.

Immunotherapy is reshaping GC management by improving survival and quality of life. Ongoing research and clinical evaluations are crucial for refining personalized and effective therapies.

Balanced self-renewal and differentiation of stem cells are crucial for maintaining tissue homeostasis, but the underlying mechanisms of this process remain poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Pax, which is orthologous to mammalian PXN, coordinates the proliferation and differentiation of ISCs during both normal homeostasis and injury-induced midgut regeneration in Drosophila. Loss of Pax promotes ISC proliferation while suppressing its differentiation into absorptive enterocytes (ECs). Mechanistically, our findings demonstrate that Pax is a conserved target gene of the Hippo signaling pathway in both Drosophila and mammals. Subsequent investigations have revealed Pax interacts with Yki and enhances its cytoplasmic localization, thereby establishing a feedback regulatory mechanism that attenuates Yki activity and ultimately inhibits ISCs proliferation. Additionally, Pax induces the differentiation of ISCs into ECs by activating Notch expression, thus facilitating the differentiation process. Overall, our study highlights Pax as a pivotal component of the Hippo and Notch pathways in regulating midgut homeostasis, shedding light on this growth-related pathway in tissue maintenance and intestinal function.

Cellular behavior is strongly influenced by mechanical signals in the surrounding microenvironment, along with external factors such as temperature fluctuations, changes in blood flow, and muscle activity, etc. These factors are key in shaping cellular states and can contribute to the development of various diseases. In the realm of rehabilitation physical therapies, therapeutic exercise and manual treatments, etc., are frequently employed, not just for pain relief but also to support recovery from diverse health conditions. However, the detailed molecular pathways through which these therapies interact with tissues and influence gene expression are not yet fully understood. The identification of YAP has been instrumental in closing this knowledge gap. YAP is known for its capacity to perceive and translate mechanical signals into specific transcriptional programs within cells. This insight has opened up new perspectives on how physical and rehabilitation medicine may exert its beneficial effects. The review investigates the involvement of the Hippo/YAP signaling pathway in various diseases and considers how different rehabilitation techniques leverage this pathway to aid in healing. Additionally, it examines the therapeutic potential of modulating the Hippo/YAP pathway within the context of rehabilitation, while also addressing the challenges and controversies that surround its use in physical and rehabilitation medicine.

The purpose of this review is to explore the molecular foundations of ocular surface squamous neoplasia (OSSN), focusing on the genetic and epigenetic aspects. While current management strategies include surgical excision and medical therapies, the understanding of OSSN's molecular basis remains limited, hindering the development of targeted treatments.

A comprehensive MEDLINE search was conducted for literature published between January 1993 and October 2023. Only studies with original data on molecular, genetic, or epigenetic mechanisms, such as mutations, gene expression, and genetic predispositions were included. Articles were excluded if they focused solely on clinical management without addressing these factors, or if they were reviews, editorials, or opinion pieces.

The search yielded a total of 108 articles, out of which 39 articles met the criteria for further analysis. Investigations into OSSN have identified key DNA mutations in the TP53, HGF, EGFR, TERT, and CDKN2A genes, indicating common oncogenic pathways shared with other squamous cell carcinomas (SCCs). Significant epigenetic changes were identified, including DNA methylation, histone modifications, and altered miRNA expression patterns. Epigenetic dysregulation of critical tumor suppressors and oncoproteins, further highlight the complex genetic landscape of OSSN.

The molecular alterations identified in OSSN not only enhance our understanding of its biology but also have potential as novel biomarkers for early detection, prognostic evaluation, and as therapeutic targets. The identification of genetic and epigenetic markers in OSSN signifies progress towards personalized medicine approaches. Further studies and collaborative efforts are essential to validate these molecular markers and translate them into clinical practice, potentially revolutionizing OSSN management and improving patient outcomes.

The Yes-associated protein (YAP) oncoprotein has been linked to both metastases and resistance to targeted therapy of lung cancer cells. We aimed to investigate the effect of YAP pharmacological inhibition, using YAP/TEA domain (TEAD) transcription factor interaction inhibitors in chemo-resistant lung cancer cells. YAP subcellular localization, as a readout for YAP activation, cell migration, and TEAD transcription factor functional transcriptional activity were investigated in cancer cell lines with up-regulated YAP, with and without YAP/TEAD interaction inhibitors. Parental (A549) and paclitaxel-resistant (A549R) cell transcriptomes were analyzed. The half-maximal inhibitory concentration (IC50) of paclitaxel or trametinib, which are Mitogen-Activated protein kinase and Erk Kinase (MEK) inhibitors, combined with a YAP/TEAD inhibitor (IV#6), was determined. A three-dimensional (3D) microfluidic culture device enabled us to study the effect of IV#6/paclitaxel combination on cancer cells isolated from fresh resected lung cancer samples. YAP activity was significantly higher in paclitaxel-resistant cell lines. The YAP/TEAD inhibitor induced a decreased YAP activity in A549, PC9, and H2052 cells, with reduced YAP nuclear staining. Wound healing assays upon YAP inhibition revealed impaired cell motility of lung cancer A549 and mesothelioma H2052 cells. Combining YAP pharmacological inhibition with trametinib in K-Ras mutated A549 cells recapitulated synthetic lethality, thereby sensitizing these cells to MEK inhibition. The YAP/TEAD inhibitor lowered the IC50 of paclitaxel in A549R cells. Differential transcriptomic analysis of parental and A549R cells revealed an increased YAP/TEAD transcriptomic signature in resistant cells, downregulated upon YAP inhibition. The YAP/TEAD inhibitor restored paclitaxel sensitivity of A549R cells cultured in a 3D microfluidic system, with lung cancer cells from a fresh tumor efficiently killed by YAP/TEAD inhibitor/paclitaxel doublet. Evidence of the YAP/TEAD transcriptional program's role in chemotherapy resistance paves the way for YAP therapeutic targeting.

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.

The Hippo-yes-associated protein (YAP) signaling pathway plays a crucial role in cell proliferation, differentiation, and death. It is known to have impact on the progression and development of cardiovascular diseases (CVDs) as well as in the regeneration of cardiomyocytes (CMs). However, further research is needed to understand the molecular mechanisms by which the Hippo-YAP pathway affects the pathological processes of CVDs in order to evaluate its potential clinical applications. In this review, we have summarized the recent findings on the role of the Hippo-YAP pathway in CVDs such as myocardial infarction, heart failure, and cardiomyopathy, as well as its in CM development. This review calls attention to the potential roles of the Hippo-YAP pathway as a relevant target for the future treatment of CVDs.

Naive pluripotent stem cells have the highest developmental potential but their in vivo existence in the blastocyst is transient. Here we report a blastocyst motif substrate for the in vitro reversion of mouse and human pluripotent stem cells to a naive state. The substrate features randomly varied microstructures, which we call motifs, mimicking the geometry of the blastocyst. Motifs representing mouse-blastocyst-scaled curvature ranging between 15 and 62 mm-1 were the most efficient in promoting reversion to naivety, as determined by time-resolved correlative analysis. In these substrates, apical constriction enhances E-cadherin/RAC1 signalling and activates the mechanosensitive nuclear transducer YAP, promoting the histone modification of pluripotency genes. This results in enhanced levels of pluripotency transcription factor NANOG, which persist even after cells are removed from the substrate. Pluripotent stem cells cultured in blastocyst motif substrates display a higher development potential in generating embryoid bodies and teratomas. These findings shed light on naivety-promoting substrate design and their large-scale implementation.

Sevoflurane is a widely used inhalation anesthetic associated with neuronal damage, cognitive impairment and neurodegenerative diseases, with iron overload reported to contribute to these adverse effects. However, the mechanisms of iron-dependent cell death (ferroptosis) in sevoflurane-induced neurotoxicity remain poorly understood.

The role of PLIN4, a protein associated with neurodegeneration, in sevoflurane-induced neuronal damage was investigated using cultured mouse hippocampal neurons (HT22). PLIN4 knockdown or overexpression was performed through vector transfection, and PLIN4 transcription and expression levels after sevoflurane treatment and knockdown experiments were assessed via RT-qPCR, immunostaining, and western blot to evaluate its impact on ferroptosis. Transmission electron microscopy was used to assess cellular morphology and measure Fe2+ levels.

Sevoflurane treatment significantly increased PLIN4 expression in hippocampal neurons and induced ferroptosis. Silencing PLIN4 reduced ferroptosis and partially reversed sevoflurane's inhibition of the Hippo signaling pathway. Specifically, sevoflurane treatment led to a 2.9-fold increase in PLIN4 mRNA levels. Furthermore, higher PLIN4 levels upregulated ferroptosis in hippocampal neurons by inhibiting the Hippo pathway.

Our study indicates that sevoflurane promotes ferroptosis in neurons by upregulating PLIN4 and modulating the Hippo signaling pathway. These findings provide insights into the potential development of interventions to prevent anesthesia-related cognitive impairments and neurodegeneration.

As one of the most prevalent malignant neoplasms among women globally, the optimization of therapeutic strategies for breast cancer has perpetually been a research hotspot. The tumor microenvironment (TME) is of paramount importance in the progression of breast cancer, among which the extracellular matrix (ECM) and hypoxia are two crucial factors. The alterations of these two factors are predominantly regulated by the Hippo signaling pathway, which promotes tumor invasiveness, metastasis, therapeutic resistance, and susceptibility. Hence, this review focuses on the Hippo pathway in breast cancer, specifically, how the ECM and hypoxia impact the biological traits and therapeutic responses of breast cancer. Moreover, the role of miRNAs in modulating ECM constituents was investigated, and hsa-miR-33b-3p was identified as a potential therapeutic target for breast cancer. The review provides theoretical foundations and potential therapeutic direction for clinical treatment strategies in breast cancer, with the aspiration of attaining more precise and effective treatment alternatives in the future.

Colon adenocarcinoma (COAD) ranks as the third most prevalent and lethal cancer in 2020, with metastasis being the primary cause of cancer-related mortality. A comprehensive understanding of the mechanism underlying distant metastasis is imperative for enhancing the prognosis and quality of life of patients with COAD.

This study employed gene set enrichment analysis (GSEA) on RNA-sequencing data from 408 patients with COAD in The Cancer Genome Atlas (TCGA) database. GSEA analysis was applied to find the significant hallmark gene set, and genes in the significant hallmark gene set was performed by univariate Cox regression to select the key gene. Then, multivariate Cox regression model was constructed. And various databases were utilized to validate and find the significant oncoprotein and hallmark gene set of the key gene. In addition, the expression of key regulators in para-carcinoma tissue, colon cancer and distant metastases samples were detected by real-time PCR, Immunohistochemistry and Western blot. Additionally, the biological functions were examined by in vitro and in vivo experiments. The scRNA-seq and CellphoneDB were performed to explore cell characters in COAD and the potential mechanism of metastasis.

The regulatory network analysis revealed SRC/YAP1 as the most significant oncoprotein and signature gene set associated with SNTB1. Moreover, significant SNTB1 overexpression in COAD metastatic tissues was observed compared to para-carcinoma and primary COAD tissues. Co-immunoprecipitation assays demonstrated the formation of a complex between SNTB1 and SRC proteins. Furthermore, the overexpression of SNTB1 enhanced the proliferation, migration and invasion capacities of COAD cell lines. Caudal vein injection of COAD cells overexpressing SNTB1 in nude mice resulted in increased tumour growth and metastasis to the lung, liver and bone. Finally, single cell RNA-seq revealed alterations in the cellular subtypes of COAD, and CellphoneDB indicated that the interaction between cancer cells exhibiting high SNTB1 expression and enterocytes promoted EMT through cellular communications involving TGF-β, accelerating metastasis in COAD.

This study postulates that SNTB1 interacts with SRC to activate the Hippo-YAP pathway, thereby promoting COAD metastasis. Furthermore, cellular communication with enterocytes promotes EMT, facilitating metastasis. These findings propose novel therapeutic targets for preventing or treating metastatic COAD.

Non-small cell lung cancer (NSCLC) collective invasion is supported by cooperativity of proliferative (follower) and invasive (leader) cells. H1299-isolated follower cells exhibit higher Yes-associated protein (YAP) expression, while leader cells were found to express elevated transcriptional coactivator with PDZ-binding motif (TAZ/WWTR1) expression. Suppressing TAZ (not YAP) in leader cells reduced invasion. TAZ-regulated leader cell invasion is associated with activation of the EGFR-PI3K-AKT axis. NSCLC patient samples also demonstrated heterogeneity in YAP and TAZ expression. YAP and TAZ regulate proliferation of follower and leader cells. Our results highlight the need to inhibit both YAP and TAZ to effectively target their regulation of collective invasion. We identify that the SUMOylation inhibitor TAK-981 reduces YAP and TAZ expression, decreasing tumor burden and metastasis in a murine NSCLC model. Our study reveals an intra-tumoral division of labor, driven by differential YAP and TAZ expression, which can be effectively targeted with TAK-981 for NSCLC therapy.

The Hippo pathway is highly evolved to maintain tissue homeostasis in diverse species by regulating cell proliferation, differentiation, and apoptosis. In tumor biology, the Hippo pathway is a prime example of signaling molecules involved in cancer progression and metastasis. Hippo core elements LATS1, LATS2, MST1, YAP, and TAZ have critical roles in the maintenance of traditional tissue architecture and cell homeostasis. However, in cancer development, dysregulation of Hippo signaling results in tumor progression and the formation secondary cancers. Hippo components not only transmit biochemical signals but also act as mediators of mechanotransduction pathways during malignant neoplasm development and metastatic disease. This review confers knowledge of Hippo pathway core components and their role in cancer progression and metastasis and highlights the clinical role of Hippo pathway in cancer treatment. The Hippo signaling pathway and its unresolved mechanisms hold great promise as potential therapeutic targets in the emerging field of metastatic cancer research.

The self-renewal and regeneration of intestinal epithelium are mainly driven by intestinal stem cells resided in crypts, which are crucial for rapid recovery intestinal tissue following injury. Latexin (LXN) is a highly expressed stem cell proliferation and differentiation related gene in intestinal tissue. However, it is still ambiguous whether LXN participates in intestine regeneration by regulating intestinal stem cells (ISCs). Here, we report that LXN colocalizes with Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) in intestinal crypts, and deletion of LXN upregulates the expression of Lgr5 in intestinal crypts. LXN deficiency promotes the proliferation of ISCs, thereby enhances the development of intestinal organoids. Mechanically, we show that LXN deficiency enhances the expression of Lgr5 in ISCs by activating the Yes-associated protein (YAP) and wingless (Wnt) signal pathways, thus accelerating intestinal normal growth and regeneration post-injury. In summary, these findings uncover a novel function of LXN in intestinal regeneration post-injury and intestinal organogenesis, suggesting the potential role of LXN in the treatment of inflammatory bowel diseases.

The first lineage differentiation in mammals gives rise to the inner cell mass and the trophectoderm (TE). In mice, TEAD4 is a master regulator of TE commitment, as it regulates the expression of other TE-specific genes and its ablation prevents blastocyst formation, but its role in other mammals remains unclear. Herein, we have observed that TEAD4 ablation in two phylogenetically distant species (bovine and rabbit) does not impede TE differentiation, blastocyst formation and the expression of TE markers, such as GATA3 and CDX2, although a reduced number of cells in the inner cell mass was observed in bovine TEAD4 knockout (KO) blastocysts. Transcriptional analysis in bovine blastocysts revealed no major transcriptional effect of the ablation, although the expression of hypoblast and Hippo signalling-related genes tended to be decreased in KO embryos. Experiments were conducted in the bovine model to determine whether TEAD4 was required for post-hatching development. TEAD4 KO spherical conceptuses showed normal development of the embryonic disc and TE, but hypoblast migration rate was reduced. At later stages of development (tubular conceptuses), no differences were observed between KO and wild-type conceptuses.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.

In cancer research, oncogenesis can be affected by modulating the deubiquitination pathway. Ubiquitination regulates proteins post-translationally in variety of physiological processes. The Otubain Subfamily includes OTUB1 (ovarian tumor-associated proteinase B1) and OTUB2(ovarian tumor-associated proteinase B2). They are deubiquitinating enzymes, which are research hotspots in tumor immunotherapy, with their implications extending across the spectrum of tumor development. Understanding their important role in tumorigenesis, includ-ing hepatocellular carcinoma (HCC) is crucial. HCC has alarming global incidence rates and mortality statistics, ranking among the top five prevalent cancers in Malaysia1. Numerous studies have consistently indicated significant expression of OTUB1 and OTUB2 in HCC cells. In addition, OTUB1 has important biological functions in cancer, suggesting its important role in tumorigenesis. However, the mechanism underlying the action of OTUB1 and OTUB2 in liver cancer remains inadequately explored. Therefore, Otubain Subfamily, as potential molecular target, holds promise for advancing HCC treatments. However, further clinical studies are required to verify its efficacy and application prospects.

The protein menin is encoded by the MEN1 gene and primarily serves as a nuclear scaffold protein, regulating gene expression through its interaction with and regulation of chromatin modifiers and transcription factors. While the scope of menin's functions continues to expand, one area of growing investigation is the role of menin in cancer. Menin is increasingly recognized for its dual function as either a tumor suppressor or a tumor promoter in a highly tumor-dependent and context-specific manner. While menin serves as a suppressor of neuroendocrine tumor growth, as seen in the cancer risk syndrome multiple endocrine neoplasia type 1 (MEN1) syndrome caused by pathogenic germline variants in MEN1, recent data demonstrate that menin also suppresses cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, and melanoma. On the other hand, menin can also serve as a tumor promoter in leukemia, colorectal cancer, ovarian and endometrial cancers, Ewing sarcoma, and gliomas. Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin's function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation.

Rationale: Macrophage polarization plays an important role in the inflammatory regulation of ulcerative colitis (UC). In this context, necroptosis is a type of cell death that regulates intestinal inflammation, and selenoprotein S (SelS) is a selenoprotein expressed in intestinal epithelial cells and macrophages that prevents intestinal inflammation. However, the underlying mechanisms of SelS in both cell types in regulating UC inflammatory responses remain unclear. Therefore, the direct effect of SelS deficiency on necroptosis in colonic epithelial cells (CECs) was investigated. In addition, whether SelS knockdown exacerbated intestinal inflammation by modulating macrophage polarization to promote necroptosis in CECs was assessed. Methods: The UC model of SelS knockdown mice was established with 3.5% sodium dextran sulfate, and clinical indicators and colon injury were evaluated in the mice. Moreover, SelS knockdown macrophages and CECs cultured alone/cocultured were treated with IL-1β. The M1/M2 polarization, NF-κB/NLRP3 signaling pathway, oxidative stress, necroptosis, inflammatory cytokine, and tight junction indicators were analyzed. In addition, co-immunoprecipitation, liquid chromatography-mass spectrometry, laser confocal analysis, and molecular docking were performed to identify the interacting proteins of SelS. The GEO database was used to assess the correlation of SelS and its target proteins with macrophage polarization. The intervention effect of four selenium supplements on UC was also explored. Results: Ubiquitin A-52 residue ribosomal protein fusion product 1 (Uba52) was identified as a potential interacting protein of SelS and SelS, Uba52, and yes-associated protein (YAP) was associated with macrophage polarization in the colon tissue of patients with UC. SelS deficiency in CECs directly induced reactive oxygen species (ROS) production, necroptosis, cytokine release, and tight junction disruption. SelS deficiency in macrophages inhibited YAP ubiquitination degradation by targeting Uba52, promoted M1 polarization, and activated the NF-κB/NLRP3 signaling pathway, thereby exacerbating ROS-triggered cascade damage in CECs. Finally, exogenous selenium supplementation could effectively alleviate colon injury in UC. Conclusion: SelS is required for maintaining intestinal homeostasis and that its deletion enhances necroptosis in CECs, which is further exacerbated by promoting M1 macrophage polarization, and triggers more severe barrier dysfunction and inflammatory responses in UC.