The interaction between intratumoral bacteria and metabolic distortion in hepatocellular carcinoma.

BACKGROUND: Intratumoral bacteria might play essential roles in tumorigenesis in different cancer types. However, its features and potential roles in hepatocellular carcinoma (HCC) are largely unknown. METHODS: In this study, we assessed bacterial RNA by 16S rRNA fluorescence in situ hybridization and detected bacterial lipopolysaccharide (LPS) via immunohistochemistry. Hepa1-6 cells were used to establish orthotopic HCC models in mice. 2bRAD sequencing for microbiome was performed to determine the intratumoral bacterial characteristics, and liquid chromatography-mass spectrometry was conducted to explore the metabolic profile. The potential association between different intratumoral microbiota and metabolites were evaluated. RESULTS: We detected bacterial 16S rRNA and LPS in HCC tissues from the patients with HCC. In HCC mouse model, we found that the intratumor bacteria in HCC tissues were significantly different to adjacent nontumor tissues. Furthermore, we observed different metabolites in HCC tissues and adjacent nontumor tissues, such as N-acetyl-D-glucosamine and a-lactose. Our results showed that several bacteria were significantly associated with metabolites, such as Pseudomonas koreensis, which was positively correlated with N-acetyl-D-glucosamine and negatively correlated with citrulline. CONCLUSIONS: This study confirmed the close association between different bacteria and metabolites, which might provide novel opportunities for developing new biomarkers and therapeutic targets for HCC.

Administration of A. muciniphila ameliorates pulmonary arterial hypertension by targeting miR-208a-3p/NOVA1 axis.

Pulmonary arterial hypertension (PH) is a chronic disease induced by a progressive increase in pulmonary vascular resistance and failure of the right heart function. A number of studies show that the development of PH is closely related to the gut microbiota, and lung-gut axis might be a potential therapeutic target in the PH treatment. A. muciniphila has been reported to play a critical role in treating cardiovascular disorders. In this study we evaluated the therapeutic effects of A. muciniphila against hypoxia-induced PH and the underlying mechanisms. Mice were pretreated with A. muciniphila suspension (2 × 108 CFU in 200 µL sterile anaerobic PBS, i.g.) every day for 3 weeks, and then exposed to hypoxia (9% O2) for another 4 weeks to induce PH. We showed that A. muciniphila pretreatment significantly facilitated the restoration of the hemodynamics and structure of the cardiopulmonary system, reversed the pathological progression of hypoxia-induced PH. Moreover, A. muciniphila pretreatment significantly modulated the gut microbiota in hypoxia-induced PH mice. miRNA sequencing analysis reveals that miR-208a-3p, a commensal gut bacteria-regulated miRNA, was markedly downregulated in lung tissues exposed to hypoxia, which was restored by A. muciniphila pretreatment. We showed that transfection with miR-208a-3p mimic reversed hypoxia-induced abnormal proliferation of human pulmonary artery smooth muscle cells (hPASMCs) via regulating the cell cycle, whereas knockdown of miR-208a-3p abolished the beneficial effects of A. muciniphila pretreatment in hypoxia-induced PH mice. We demonstrated that miR-208a-3p bound to the 3'-untranslated region of NOVA1 mRNA; the expression of NOVA1 was upregulated in lung tissues exposed to hypoxia, which was reversed by A. muciniphila pretreatment. Furthermore, silencing of NOVA1 reversed hypoxia-induced abnormal proliferation of hPASMCs through cell cycle modulation. Our results demonstrate that A. muciniphila could modulate PH through the miR-208a-3p/NOVA1 axis, providing a new theoretical basis for PH treatment.

Tryptophan metabolism in health and disease.

Tryptophan (Trp) metabolism primarily involves the kynurenine, 5-hydroxytryptamine, and indole pathways. A variety of bioactive compounds produced via Trp metabolism can regulate various physiological functions, including inflammation, metabolism, immune responses, and neurological function. Emerging evidence supports an intimate relationship between Trp metabolism disorder and diseases. The levels or ratios of Trp metabolites are significantly associated with many clinical features. Additionally, studies have shown that disease progression can be controlled by modulating Trp metabolism. Indoleamine-2,3-dioxygenase, Trp-2,3-dioxygenase, kynurenine-3-monooxygenase, and Trp hydroxylase are the rate-limiting enzymes that are critical for Trp metabolism. These key regulatory enzymes can be targeted for treating several diseases, including tumors. These findings provide novel insights into the treatment of diseases. In this review, we have summarized the recent research progress on the role of Trp metabolites in health and disease along with their clinical applications.

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer.

The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT-related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

Health and Disease: Akkermansia muciniphila, the Shining Star of the Gut Flora.

Akkermansia muciniphila (A. muciniphila) has drawn much attention as an important gut microbe strain in recent years. A. muciniphila can influence the occurrence and development of diseases of the endocrine, nervous, digestive, musculoskeletal, and respiratory systems and other diseases. It can also improve immunotherapy for some cancers. A. muciniphila is expected to become a new probiotic in addition to Lactobacillus and Bifidobacterium. An increase in A. muciniphila abundance through direct or indirect A. muciniphila supplementation may inhibit or even reverse disease progression. However, some contrary findings are found in type 2 diabetes mellitus and neurodegenerative diseases, where increased A. muciniphila abundance may aggravate the diseases. To enable a more comprehensive understanding of the role of A. muciniphila in diseases, we summarize the relevant information on A. muciniphila in different systemic diseases and introduce regulators of A. muciniphila abundance to promote the clinical transformation of A. muciniphila research.

Effects of 3-HAA on HCC by Regulating the Heterogeneous Macrophages-A scRNA-Seq Analysis.

Kynurenine derivative 3-hydroxyanthranilic acid (3-HAA) is known to regulate the immune system and exhibit anti-inflammatory activity by inhibiting T-cell cytokine secretion and influencing macrophage activity. However, the definite role of 3-HAA in the immunomodulation of hepatocellular carcinoma (HCC) is largely unexplored. An orthotopic HCC model and treated with 3-HAA by intraperitoneal injection is developed. Furthermore, cytometry by time-of-flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) analyses are carried out to define the immune landscape of HCC. It is found that 3-HAA treatment can significantly suppress tumor growth in the HCC model and alter the level of various cytokines in plasma. CyTOF data shows that 3-HAA significantly increases the percentage of F4/80hi CX3CR1lo Ki67lo MHCIIhi macrophages and decreases the percentage of F4/80lo CD64+ PD-L1lo macrophages. scRNA-seq analyses demonstrate that 3-HAA treatment is proved to regulate the function of M1 macrophages, M2 macrophages, and proliferating macrophages. Notably, 3-HAA inhibits the proinflammatory factors TNF and IL-6 in multiple cell subsets, including resident macrophages, proliferating macrophages, and pDCs. This study reveals the landscape of immune cell subsets in HCC in response to 3-HAA, indicating that 3-HAA may be a promising therapeutic target for HCC.

Current understanding of the intratumoral microbiome in various tumors.

It is estimated that in the future, the number of new cancer cases worldwide will exceed the 19.3 million recorded in 2020, and the number of deaths will exceed 10 million. Cancer remains the leading cause of human mortality and lagging socioeconomic development. Intratumoral microbes have been revealed to exist in many cancer types, including pancreatic, colorectal, liver, esophageal, breast, and lung cancers. Intratumoral microorganisms affect not only the host immune system, but also the effectiveness of tumor chemotherapy. This review concentrates on the characteristics and roles of intratumoral microbes in various tumors. In addition, the potential of therapies targeting intratumoral microbes, as well as the main challenges currently delaying these therapies, are explored. Furthermore, we briefly summarize existing technical methods used to characterize intratumoral microbes. We hope to provide ideas for exploring intratumoral microbes as potential biomarkers and targets for tumor diagnosis, treatment, and prognostication.

Prediction of hepatocellular carcinoma prognosis and immunotherapeutic effects based on tryptophan metabolism-related genes.

BACKGROUND: L-tryptophan (Trp) metabolism involved in mediating tumour development and immune suppression. However, comprehensive analysis of the role of the Trp metabolism pathway is still a challenge. METHODS: We downloaded Trp metabolism-related genes' expression data from different public databases, including TCGA, Gene Expression Omnibus (GEO) and Hepatocellular Carcinoma Database (HCCDB). And we identified two metabolic phenotypes using the ConsensusClusterPlus package. Univariate regression analysis and lasso Cox regression analysis were used to establish a risk model. CIBERSORT and Tracking of Indels by DEcomposition (TIDE) analyses were adopted to assess the infiltration abundance of immune cells and tumour immune escape. RESULTS: We identified two metabolic phenotypes, and patients in Cluster 2 (C2) had a better prognosis than those in Cluster 1 (C1). The distribution of clinical features between the metabolic phenotypes showed that patients in C1 tended to have higher T stage, stage, grade, and death probability than those of patients in C2. Additionally, we screened 739 differentially expressed genes (DEGs) between the C1 and C2. We generated a ten-gene risk model based on the DEGs, and the area under the curve (AUC) values of the risk model for predicting overall survival. Patients in the low-risk subgroup tended to have a significantly longer overall survival than that of those in the high-risk group. Moreover, univariate analysis indicated that the risk model was significantly correlated with overall survival. Multivariate analysis showed that the risk model remained an independent risk factor in hepatocellular carcinoma (p < 0.0001). CONCLUSIONS: We identified two metabolic phenotypes based on genes of the Trp metabolism pathway, and we established a risk model that could be used for predicting prognosis and guiding immunotherapy in patients with hepatocellular carcinoma.

Change of Rice Paddy and Its Impact on Human Well-Being from the Perspective of Land Surface Temperature in the Northeastern Sanjiang Plain of China.

Large-scale and high-speed paddy land expansion has appeared in Northeast China since the 21st century, causing the change in land surface temperature. The lack of continuous investigation limits the exploration of discoveries in this region. To address this limitation, a collaborative approach that combined human-computer interaction technology, gravity center model and spatial analysis was established. It provided some new findings in spatiotemporal evolution, migration trajectory and surface cooling effect of the paddy field in Northeastern Sanjiang Plain, a center of paddy field planting in China. The results show that: (1) A sustained paddy expansion was monitored, with a total area ranging from 2564.58 km2 to 11430.94 km2, along with a rate of growth of 345.72% from 2000 to 2020. Correspondingly, its reclamation rate changed to 47.53% from 10.66%, showing the improved planting level of the paddy field. (2) Gravity center of paddy field continued to be revealed northward with a 5-year interval from 2000 to 2020. Migration distance of the straight line reached 23.94 km2, with the direction offset of 27.20° from east to north. (3) Throughout the growing season of crops, the land surface temperature of paddy field was 27.73°, 29.38°, 27.01°, 25.62° and 22.97° from May to October; and the cooling temperature effect of paddy field was investigated, with the reduced values of 0.61°, 0.79° and 1.10° in the low-, medium- and high-paddy field density regions from 2000 to 2020, respectively. Overall, these new findings in the cold temperate zone, high latitude region of the Northern Hemisphere, provided the reference for the investigation of paddy field monitoring and its environmental effects in China and other regions.

A Novel Deep Transfer Learning Method for Intelligent Fault Diagnosis Based on Variational Mode Decomposition and Efficient Channel Attention.

In recent years, deep learning has been applied to intelligent fault diagnosis and has achieved great success. However, the fault diagnosis method of deep learning assumes that the training dataset and the test dataset are obtained under the same operating conditions. This condition can hardly be met in real application scenarios. Additionally, signal preprocessing technology also has an important influence on intelligent fault diagnosis. How to effectively relate signal preprocessing to a transfer diagnostic model is a challenge. To solve the above problems, we propose a novel deep transfer learning method for intelligent fault diagnosis based on Variational Mode Decomposition (VMD) and Efficient Channel Attention (ECA). In the proposed method, the VMD adaptively matches the optimal center frequency and finite bandwidth of each mode to achieve effective separation of signals. To fuse the mode features more effectively after VMD decomposition, ECA is used to learn channel attention. The experimental results show that the proposed signal preprocessing and feature fusion module can increase the accuracy and generality of the transfer diagnostic model. Moreover, we comprehensively analyze and compare our method with state-of-the-art methods at different noise levels, and the results show that our proposed method has better robustness and generalization performance.

The functional roles of the circRNA/Wnt axis in cancer.

CircRNAs, covalently closed noncoding RNAs, are widely expressed in a wide range of species ranging from viruses to plants to mammals. CircRNAs were enriched in the Wnt pathway. Aberrant Wnt pathway activation is involved in the development of various types of cancers. Accumulating evidence indicates that the circRNA/Wnt axis modulates the expression of cancer-associated genes and then regulates cancer progression. Wnt pathway-related circRNA expression is obviously associated with many clinical characteristics. CircRNAs could regulate cell biological functions by interacting with the Wnt pathway. Moreover, Wnt pathway-related circRNAs are promising potential biomarkers for cancer diagnosis, prognosis evaluation, and treatment. In our review, we summarized the recent research progress on the role and clinical application of Wnt pathway-related circRNAs in tumorigenesis and progression.

Role of main RNA modifications in cancer: N6-methyladenosine, 5-methylcytosine, and pseudouridine.

Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N6-methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.

The Mechanism Underlying the ncRNA Dysregulation Pattern in Hepatocellular Carcinoma and Its Tumor Microenvironment.

HCC is one of the most common malignant tumors and has an extremely poor prognosis. Accumulating studies have shown that noncoding RNA (ncRNA) plays an important role in hepatocellular carcinoma (HCC) development. However, the details of the related mechanisms remain unclear. The heterogeneity of the tumor microenvironment (TME) calls for ample research with deep molecular characterization, with the hope of developing novel biomarkers to improve prognosis, diagnosis and treatment. ncRNAs, particularly microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have been found to be correlated with HCC neogenesis and progression. In this review, we summarized the aberrant epigenetic and genetic alterations caused by dysregulated ncRNAs and the functional mechanism of classical ncRNAs in the regulation of gene expression. In addition, we focused on the role of ncRNAs in the TME in the regulation of tumor cell proliferation, invasion, migration, immune cell infiltration and functional activation. This may provide a foundation for the development of promising potential prognostic/predictive biomarkers and novel therapies for HCC patients.

Expression and Functional Roles of Eukaryotic Initiation Factor 4A Family Proteins in Human Cancers.

The dysregulation of mRNA translation is common in malignancies and may lead to tumorigenesis and progression. Eukaryotic initiation factor 4A (eIF4A) proteins are essential for translation, exhibit bidirectional RNA helicase function, and act as RNA-dependent ATPases. In this review, we explored the predicted structures of the three eIF4A isoforms (eIF4A1, eIF4A2, and eIF4A3), and discussed possible explanations for which function during different translation stages (initiation, mRNA localization, export, and mRNA splicing). These proteins also frequently served as targets of microRNAs (miRNAs) or long noncoding RNAs (lncRNAs) to mediate epithelial-mesenchymal transition (EMT), which was associated with tumor cell invasion and metastasis. To define the differential expression of eIF4A family members, we applied the Tumor Immune Estimation Resource website. We figured out that the eIF4A family genes were differently expressed in specific cancer types. We also found that the level of the eIF4A family genes were associated with abundant immune cells infiltration and tumor purity. The associations between eIF4A proteins and cancer patient clinicopathological features suggested that eIF4A proteins might serve as biomarkers for early tumor diagnosis, histological classification, and clinical grading/staging, providing new tools for precise and individualized cancer treatment.

ALKBH5-mediated m6A mRNA methylation governs human embryonic stem cell cardiac commitment.

N6-methyladenosine (m6A), as the most abundant modification of mammalian messenger RNAs, is essential for tissue development and pathogenesis. However, the biological significance of m6A methylation in cardiac differentiation and development remains largely unknown. Here, we identify that the downregulation of m6A demethylase ALKBH5 is responsible for the increase of m6A methylation and cardiomyocyte fate determination of human embryonic stem cells (hESCs) from mesoderm cells (MESs). In contrast, ALKBH5 overexpression remarkably blocks cardiomyocyte differentiation of hESCs. Mechanistically, KDM5B and RBBP5, the components of H3K4 modifying enzyme complexes, are identified as downstream targets for ALKBH5 in cardiac-committed hESCs. Loss of function of ALKBH5 alters the expression of KDM5B and RBBP5 through impairing stability of their mRNAs, which in turn promotes the transcription of GATA4 by enhancing histone H3 Lys4 trimethylation (H3K4me3) at the promoter region of GATA4. Taken together, we reveal a previously unidentified role of m6A demethylase ALKBH5 in determining cardiac lineage commitment of hESCs.

Mitochondrial pyruvate carrier 1: a novel prognostic biomarker that predicts favourable patient survival in cancer.

Mitochondrial pyruvate carrier 1 (MPC1) is a key metabolic protein that regulates the transport of pyruvate into the mitochondrial inner membrane. MPC1 deficiency may cause metabolic reprogramming. However, whether and how MPC1 controls mitochondrial oxidative capacity in cancer are still relatively unknown. MPC1 deficiency was recently found to be strongly associated with various diseases and cancer hallmarks. We utilized online databases and uncovered that MPC1 expression is lower in many cancer tissues than in adjacent normal tissues. In addition, MPC1 expression was found to be substantially altered in five cancer types: breast-invasive carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and prostate adenocarcinoma (PRAD). However, in KIRC, LUAD, PAAD, and PRAD, high MPC1 expression is closely associated with favourable prognosis. Low MPC1 expression in BRCA is significantly associated with shorter overall survival time. MPC1 expression shows strong positive and negative correlations with immune cell infiltration in thymoma (THYM) and thyroid carcinoma (THCA). Furthermore, we have comprehensively summarized the current literature regarding the metabolic reprogramming effects of MPC1 in various cancers. As shown in the literature, MPC1 expression is significantly decreased in cancer tissue and associated with poor prognosis. We discuss the potential metabolism-altering effects of MPC1 in cancer, including decreased pyruvate transport ability; impaired pyruvate-driven oxidative phosphorylation (OXPHOS); and increased lactate production, glucose consumption, and glycolytic capacity, and the underlying mechanisms. These activities facilitate tumour progression, migration, and invasion. MPC1 is a novel cancer biomarker and potentially powerful therapeutic target for cancer diagnosis and treatment. Further studies aimed at slowing cancer progression are in progress.

Oncogenic roles and mechanisms of lncRNA AGAP2-AS1 in human solid tumors.

Cancer remains the second leading life-threatening disease worldwide. Increasing evidence indicates that long non-coding RNAs (lncRNAs) play an important role in multiple physiological and pathological processes, including gene amplification, mutation, rearrangement, and overexpression regulations. In this review, we comprehensively summarize the current knowledge of lncRNA AGAP2-AS1 from a cancer perspective. As a member of the lncRNA family, lncRNA AGAP2-AS1 is upregulated in solid tumor malignancies, functions as an oncogene, and plays a key role in tumorigenesis and tumor progression. AGAP2-AS1 expression is significantly increased in clinical cancer tissue samples, cell lines, and in vivo, and is closely related to an unfavorable prognosis in several cancers. Upregulated lncRNA AGAP2-AS1 binds with microRNAs (miRNAs) and promotes activation of downstream genes. This aberrant regulation induces carcinogenesis and tumorigenesis. Here we provide a comprehensive overview of AGAP2-AS1 in cancer progression that leads to an improved understanding of the effects of AGAP2-AS1 on early detection and therapeutic approaches. This information is essential for the future development of lncRNA AGAP2-AS1 as a potential therapy against these devastating cancers.

Mitochondrial Mechanisms of Necroptosis in Liver Diseases.

Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease. Necroptosis is a common form of programmed cell death in the liver. Necroptosis can be activated by ligands of death receptors, which then interact with receptor-interactive protein kinases 1 (RIPK1). RIPK1 mediates receptor interacting receptor-interactive protein kinases 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) and necrosome formation. Regarding the molecular mechanisms of mitochondrial-mediated necroptosis, the RIPK1/RIPK3/MLKL necrosome complex can enhance oxidative respiration and generate reactive oxygen species, which can be a crucial factor in the susceptibility of cells to necroptosis. The necrosome complex is also linked to mitochondrial components such as phosphoglycerate mutase family member 5 (PGAM5), metabolic enzymes in the mitochondrial matrix, mitochondrial permeability protein, and cyclophilin D. In this review, we focus on the role of mitochondria-mediated cell necroptosis in acute liver injury, chronic liver diseases, and hepatocellular carcinoma, and its possible translation into clinical applications.

Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity.

Ribavirin has been proven to be an antiviral treatment, whereas there are still risks of hemolysis and congenital malformation. Abnormal cardiac development contributes to the occurrence and development of many heart diseases. However, there is so far no evidence that ribavirin induces human cardiac developmental toxicity. Herein, we employed the cardiac differentiation model of human induced pluripotent stem cells (hiPSCs) to determine the impact of ribavirin on heart development. Our data showed that ribavirin at clinically high concentrations (5 and 10 µM) significantly inhibited the proliferation and differentiation of hiPSCs from mesoderm to cardiac progenitor cells and cardiac progenitor cells to cardiomyocytes, but not from pluripotent status to mesoderm. Meanwhile, DCFH-DA staining revealed that ribavirin could increase ROS content in the mid-phase of differentiation. In addition, ribavirin treatment (1, 5 and 10 µM) remarkably caused DNA damage which was shown by the increase of γH2AX-positive cells and upregulation of the p53 during the differentiation of hiPSCs from mesoderm to cardiac progenitor cells. Moreover, exposuring to ribavirin (5 and 10 µM) markedly upregulated the expression of lncRNAs Gas5 in both mid-phase and late phase of differentiation and HBL1 in the mid-phase. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage, upregulated p53 and increased Gas5. It may provide the evidence for the rational clinical application of ribavirin.

YAP/TEAD3 signal mediates cardiac lineage commitment of human-induced pluripotent stem cells.

Cardiomyocytes differentiated from human-induced pluripotent stem cells (hiPSCs) hold great potential for therapy of heart diseases. However, the underlying mechanisms of its cardiac differentiation have not been fully elucidated. Hippo-YAP signal pathway plays important roles in cell differentiation, tissue homeostasis, and organ size. Here, we identify the role of Hippo-YAP signal pathway in determining cardiac differentiation fate of hiPSCs. We found that cardiac differentiation of hiPSCs were significantly inhibited after treatment with verteporfin (a selective and potent YAP inhibitor). During hiPSCs differentiation from mesoderm cells (MESs) into cardiomyocytes, verteporfin treatment caused the cells retained in the earlier cardiovascular progenitor cells (CVPCs) stage. Interestingly, during hiPSCs differentiation from CVPC into cardiomyocytes, verteporfin treatment induced cells dedifferentiation into the earlier CVPC stage. Mechanistically, we found that YAP interacted with transcriptional enhanced associate domain transcription factor 3 (TEAD3) to regulate cardiac differentiation of hiPSCs during the CVPC stage. Consistently, RNAi-based silencing of TEAD3 mimicked the phenotype as the cells treated with verteporfin. Collectively, our study suggests that YAP-TEAD3 signaling is important for cardiomyocyte differentiation of hiPSCs. Our findings provide new insight into the function of Hippo-YAP signal in cardiovascular lineage commitment.