Scientific Reports
·
2016
·Vol. 6
·期 1
·1-12
·
IF 5.228
Zhou Tian-yi,Zhuang Lin-han,Hu Yan,Zhou Yu-lu,Lin Wen-kai,Wang Dan-dan,Wan Zi-qian,Chang Lin-lin,Chen Ying,Ying Mei-dan,Chen Zi-bo,Ye Song,Lou Jian-shu,He Qiao-jun,Zhu Hong,Yang Bo
Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro . Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients.
研究领域:
肿瘤学
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药理学
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分子生物学
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PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2026
·
IF 5.3
Xiaotian Yang,Shudan Yang,Guoqiang Lin,Shutong Chen,Huiran Jiang,Yuting Wang,Yanming Zhang,Xingxia Zhang
Aberrant activation of YAP-TEAD4 drives tumorigenesis, progression, and chemoresistance. Disrupting their interaction serves as an alternative anticancer strategy, with peptides better adapting to the large, flat interaction interface. In this study, the peptides 1–4 were screened from the peptide database via pharmacophore modelling, molecular docking, and interaction analysis. Subsequently, affinity experiments showed that among the peptides 1–4, peptide-4 possessed the lowest Kd values (Kd = 5.08 ± 0.42 nM) measured by MST and exhibited the binding affinity for TEAD4. MD simulations further demonstrated that peptide-4 stably bound to the TEAD4. MTT assays showed that peptide-4 suppressed AML-193 cell viability with an IC50 of 0.65 ± 0.04 μM. RT-qPCR assays demonstrated that Peptide-4 significantly downregulated the mRNA expression levels of CTGF and CYR61. In conclusion, the data demonstrated that the peptide-4 may serve as a promising candidate to disrupt the YAP-TEAD4 interaction and enhance biological activity in AML-related cellular models.
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Advanced Science
·
2026
·
IF 14.1
Jiawei Wang,Yaozhi He,Yanjiao Wang,Jingjing Zhang,Qishun Liang,Mengxian Jia,Yumin Wu,Zongjie Yuan,Ziwei Fan,Yuxuan Li,Huihui Zhang,Qinjiao Fu,Ying Wang,Zhihui Huang,Honglin Teng
After spinal cord injury (SCI), the blood-spinal cord barrier (BSCB) is disrupted, and endothelial cells, a critical component of BSCB, undergo proliferation and remodeling to maintain barrier integrity. However, the molecular mechanisms underlying BSCB remodeling remain unclear after SCI. Here, we reveal that Yes-associated protein (YAP), a principal downstream effector of the Hippo signaling pathway, promotes endothelial proliferation and BSCB repair in mice after SCI. First, we found that YAP expression was significantly upregulated and activated in endothelial cells after SCI. Endothelial YAP knockout (YAP TEK-cre/ERT2 -CKO mice) impaired endothelial proliferation, endothelial-astrocyte end-feet reorganization, and tight junction (TJ) integrity, thereby aggravating BSCB disruption and impairing BSCB remodeling and motor functional recovery after SCI. Mechanistically, endothelial YAP-dependent BSCB repair was associated with angiopoietin-1 (ANGPT1) expression and PI3K/AKT pathway activation after SCI. Exogenous ANGPT1 treatment mitigated YAP deficiency-induced inhibition of endothelial proliferation and endothelial barrier disruption via PI3K/AKT signaling in vitro. Finally, activation of YAP signaling partially mitigated SCI-induced BSCB disruption, ultimately improving motor function recovery. Together, these results identify endothelial YAP signaling as a critical regulator of BSCB remodeling associated with ANGPT1/PI3K/AKT pathway and provide a potential therapeutic target for SCI.
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ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Zhou Yan,Yang Yifan,Wang Yuehan,Cheang Wai San
YAP/TAZ and SMAD1/5 signaling modulate atherosclerosis. These involvements in diabetes-associated endothelial dysfunction remain unexplored, thereby being investigated from different endothelial cells and a total of 102 mice in the current study. Male C57BL/6 mice were fed a high-fat diet (45% kcal% fat, 15 weeks) and orally administered with endoplasmic reticulum (ER) stress alleviator 4-phenylbutyric acid (100 mg·kg –1 ·d –1 ) and jatrorrhizine (50 mg·kg –1 ·d –1 ) for 5 weeks. Endothelial cells were cultured with high glucose, ER stress inducer tunicamycin, ER stress alleviators, YAP inhibitor simvastatin, or jatrorrhizine. The mouse aorta was divided into the aortic arch and thoracic aorta regions to investigate the regional difference. Treatment with PBA and jatrorrhizine ameliorated endothelium-dependent relaxations as well as inhibited ER stress, YAP/TAZ-SMAD1/5 signaling and oxidative stress in aortas. Phosphorylation of YAP/TAZ was highly expressed in the thoracic aorta but low in the aortic arch. On the other hand, phosphorylation of SMAD1/5 was upregulated in the inner curvature of the aortic arch but downregulated in the thoracic aorta. In HUVECs, ER stress alleviators significantly inhibited YAP/TAZ-SMAD1/5 signaling and increased NO bioavailability, but the YAP inhibitor did not suppress ER stress. Inhibition of YAP/TAZ downregulated SMAD1/5 signaling under high glucose stimulation, followed by the Akt/eNOS pathway. YAP/TAZ directly interacts with SMAD1/5, and their binding is significantly enhanced under high-glucose conditions. A natural compound, jatrorrhizine, was identified to inhibit YAP/TAZ-SMAD1/5 signaling and protect vascular function in diabetes. To conclude, ER stress activates YAP/TAZ and SMAD1/5 signaling, resulting in endothelial dysfunction in diabetes. Inhibition of YAP/TAZ-SMAD1/5, such as by ER stress alleviators and natural product jatrorrhizine, ameliorates endothelial dysfunction associated with diabetes. These findings support the cross-talk between ER stress and YAP/TAZ-SMAD1/5 as well as their potential as therapeutic targets.
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Advanced Science
·
2025
·
IF 14.1
Ze Li,Jiayang Li,Kang Chen,Guiwen Qu,Shuanghong Yang,Sicheng Li,Ye Liu,Yitian Teng,Rui Ma,Jinjian Huang,Peige Wang,Jianan Ren,Xiuwen Wu
Intestinal fistula is a serious condition characterized by abnormal connections between the intestine and surrounding tissues. Despite advances in comprehensive management of intestinal fistulas, patients often need to undergo definitive surgery and face life-threatening complications due to ineffective closure measures. Herein, a mechanically active hydrogel (GNGP) that actively constricts intestinal fistulas in response to body temperature is presented. It possesses broad-spectrum antimicrobial properties, excellent adhesion, suitable degradation properties, and a balance between injectable properties and mechanical activity—which, together, enable the in situ sealing of intestinal fistulas. Moreover, GNGP hydrogel accelerates the re-epithelialization process of rabbit intestinal fistulas, ameliorates the inflammation of the fistula tract, and promotes the deposition of collagen into the damaged area to effectively facilitate intestinal fistula healing. Mechanistically, shear stress is found to promote the proliferation of intestinal epithelial cells via Yes-associated protein-mediated mechanosensitization, through finite element simulations and in vitro experiments. Together, this mechanically active hydrogel with injectable properties offers a promising strategy for the sealing treatment of intestinal fistulas.
研究领域:
生物材料
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组织工程
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胃肠病学
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机械生物学
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生物医学工程
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Cell Death Discovery
·
2026
·
IF 10.4
Hao Wenli,Gao Song,Guo Suhan,Luo Jingjing,Li Siyu,Lu Junze,Jiang Lulu,Lu Jie,Wang Nan,Ran Aijia,Qian Xiaoyun,Gao Xia,Yu Chenjie,Cheng Cheng
Lipid metabolism is an important biological process that maintains the dynamic balance of several key functions, such as intracellular energy metabolism, signal transduction, and membrane remodeling. However, the role of lipid metabolism in auditory function and the underlying mechanisms remain unclear. Our results reveal that the neomycin exposure disrupts lipid metabolism in auditory system. We find that neomycin-induced hair cells (HC) damage leads to abnormal lipid droplets (LD) accumulation. Further research reveals that decreased YAP expression is a key factor that contributes to abnormal LD accumulation. In both in vivo and in vitro studies, Yap overexpression reduces abnormal LD accumulation and mitigated HC damage. To further investigate its downstream mechanisms, we perform a cross-analysis of Yap -related and lipid metabolism–related genes, identifying that Cox2 is a key downstream target of Yap that contributes to LD accumulation and HC damage. Our work provides clear evidence for the role of lipid metabolism in neomycin-induced hearing loss and elucidates underlying mechanism of Yap/Cox2 pathway. These findings provide new perspectives and avenues for the clinical treatment of sensorineural hearing loss.
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ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·146-156
·
IF 6.15
Yao Xin-peng,Jiao Ting-ying,Jiang Yi-ming,Fan Shi-cheng,Zhao Ying-yuan,Yang Xiao,Gao Yue,Li Fei,Zhou Yan-ying,Chen Pan-pan,Huang Min,Bi Hui-chang
Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing’s syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice and Pxr -knockout mice. The results demonstrated that high-dose Mif (100 mg · kg −1 · d −1 , i.p .) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg −1 · d −1 , i.p .) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg −1 · d −1 , i.p .) failed to induce hepatomegaly in Pxr -knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
研究领域:
药理学
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毒理学
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分子生物学
·
肝病学
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Jin Li,Bin Zhang,Bingxin Wang,Xiaoxiao Zhang
ZDHHC15 regulates YAP localization and YAP/CYR61 signaling in OSCC. • PA supports OSCC migration through lipid metabolism-linked signaling. • R-LPA@siZDHHC15 enables targeted siRNA delivery and photothermal response. • The nanoplatform suppresses OSCC growth and lung colonization in models. This study aimed to elucidate the molecular mechanism by which ZDHHC15 promotes oral squamous cell carcinoma (OSCC) progression through regulation of the YAP/CYR61 signaling axis. Metabolomic and transcriptomic analyses revealed prominent lipid metabolic reprogramming in OSCC cells, with palmitic acid (PA) driving activation of the YAP transcriptional program and promoting cell migration and lung colonization. Functional experiments showed that ZDHHC15 enhanced YAP nuclear localization and transcriptional activity, leading to increased CYR61 expression and establishment of the ZDHHC15/YAP/CYR61 signaling axis. In addition, we developed a novel nanoplatform, R-LPA@siZDHHC15, which exhibited photothermal responsiveness and tumor-targeted delivery in vivo . When combined with photothermal therapy, this platform suppressed OSCC cell proliferation and tumor growth under the tested conditions. Collectively, these findings provide mechanistic insight into OSCC progression and support targeting the ZDHHC15/YAP/CYR61 axis as a potential therapeutic strategy, while further control and thermal-monitoring studies are needed to fully define the nanotherapeutic contribution. Schematic representation of the molecular mechanism by which R-LPA@siZDHHC15 modulates the YAP/CYR61 axis, thereby achieving combined photothermal and gene therapy to suppress OSCC progression. Download: Download high-res image (152KB) Download: Download full-size image
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 5.6
Changfu Zhang,Haichun Li,Yushuai Gao,Kaiyuan Deng,Rongjun Qian
Glioma, a highly lethal and common malignant tumor of the central nervous system, is characterized by its aggressive invasive behavior. Tumor-associated macrophage (TAM) represent the most abundant infiltrating immune cell population in the glioma microenvironment and play a critical role in gliomagenesis and progression. Although A-kinase anchoring protein 13 (AKAP13) has been implicated in other cancers, its specific role in glioma progression and TAM infiltration remains unclear. In this study, we identify AKAP13 is significantly upregulated in glioma tissues and associated with poor patient survival. Functionally, AKAP13 silencing inhibited glioma cell invasion and TAM recruitment in both in vitro and in vivo models. Mechanistically, AKAP13 drives tumor progression by enhancing YAP expression and nuclear translocation, which subsequently upregulates the TAM-recruiting chemokines CSF1 and CCL2. We further identified F-box and WD repeat domain-containing 7 (FBXW7) as an upstream regulator that promotes ubiquitin-mediated degradation of AKAP13. Together, our findings reveal a novel FBXW7/AKAP13/YAP/chemokine signaling axis that promotes glioma pathogenesis through both tumor-autonomous invasion and TAM recruitment, highlighting a promising therapeutic target for this lethal malignancy.
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DRUG METABOLISM AND DISPOSITION
·
2020
·Vol. 48
·期 9
·830-839
·
IF 3.231
Tingying Jiao,Xinpeng Yao,Yingyuan Zhao,Yanying Zhou,Yue Gao,Shicheng Fan,Panpan Chen,Xuan Li,Yiming Jiang,Xiao Yang,Frank J. Gonzalez,Min Huang,Huichang Bi
Dexamethasone (Dex), a widely prescribed anti-inflammatory drug, was reported to induce liver enlargement (hepatomegaly) in clinical practice and in animal models. However, the underlying mechanisms are not elucidated. Dex is a known activator of pregnane X receptor (PXR). Yes-associated protein (YAP) has been implicated in chemically induced liver enlargement. Here, the roles of PXR and YAP pathways were investigated in Dex-induced hepatomegaly. Upregulation of PXR downstream proteins, including cytochrome P450 (CYP) 3A11, 2B10, and organic anion transporter polypeptide 2 (OATP2) (also known as SLCO1A4 and SLC21A5 in mouse), indicated PXR signaling was activated after high dose of Dex (50 mg/kg, i.p.), and Dex at 100 μM activated PXR in the dual-luciferase reporter gene assay. Dex also increased the expression of total YAP, nuclear YAP, and YAP downstream proteins, including connective tissue growth factor and cysteine-rich angiogenic inducer 61, indicating activation of the YAP pathway. Furthermore, nuclear translocation of YAP was promoted by activation of PXR. However, hepatocyte proliferation was inhibited with significant decrease in the expression of proliferation-related proteins cyclin D1 and proliferating cell nuclear antigen as well as other regulatory factors, such as forkhead box protein M1, c-MYC, and epidermal growth factor receptor. The inhibitory effect of Dex on hepatocyte proliferation was likely due to its anti-inflammation effect of suppression of inflammation factors. β-catenin staining revealed enlarged hepatocytes, which were mostly attributable to the accumulation of lipids, such as triglycerides. In summary, high-dose Dex increased liver size accompanied by enlarged hepatocytes, and this was due to the activation of PXR/YAP and their effects on lipid accumulation but not hepatocyte proliferation. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly.
研究领域:
药理学
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肝病学
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细胞生物学
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RESPIRATORY RESEARCH
·
2022
·Vol. 23
·期 1
·1-16
·
IF 7.162
Liu Haitao,Zhang Sha,Liu Yi,Ma Jing,Chen Wei,Yin Tao,Li Tongbin,Liang Bin,Tao Ling
Background Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance and artery pressure. Vascular remodeling is associated with the excessive cell proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). In this paper, the effects of heat shock protein-110 (HSP110) on PH were investigated.Methods The C57BL/6 mice and human PASMCs (HPASMCs) were respectively exposed to hypoxia to establish and simulate PH model in vivo and cell experiment in vitro. To HSP110 knockdown, the hypoxia mice and HPASMCs were infected with adeno-associated virus or adenovirus carring the shRNAs (short hairpin RNAs) for HSP110 (shHSP110). For HSP110 and yes-associated protein (YAP) overexpression, HPASMCs were infected with adenovirus vector carring the cDNA of HSP110 or YAP. The effects of HSP110 on PH development in mice and cell proliferation, migration and autophagy of PASMCs under hypoxia were assessed. Moreover, the regulatory mechanisms among HSP110, YAP and TEA domain transcription factor 4 (TEAD4) were investigated.Results We demonstrated that expression of HSP110 was significantly increased in the pulmonary arteries of mice and HPASMCs under hypoxia. Moreover, knockdown of HSP110 alleviated hypoxia-induced right ventricle systolic pressure, vascular wall thickening, right ventricular hypertrophy, autophagy and proliferation of PASMCs in mice. In addition, knockdown of HSP110 inhibited the increases of proliferation, migration and autophagy of HPASMCs that induced by hypoxia in vitro. Mechanistically, HSP110 knockdown inhibited YAP and transcriptional co-activator with PDZ-binding motif (TAZ) activity and TEAD4 nuclear expression under hypoxia. However, overexpression of HSP110 exhibited the opposite results in HPASMCs. Additionally, overexpression of YAP partially restored the effects of shHSP110 on HPASMCs. The interaction of HSP110 and YAP was verified. Moreover, TEAD4 could promote the transcriptional activity of HSP110 by binding to the HSP110 promoter under hypoxia.Conclusion sOur findings suggest that HSP110 might contribute to the development of PH by regulating the proliferation, migration and autophagy of PASMCs through YAP/TAZ-TEAD4 pathway, which may help to understand deeper the pathogenic mechanism in PH development.
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Theranostics
·
2026
·Vol. 16
·期 5
·2372
·
IF 13.3
Jiawen Chen,Junfeng Liu,Xiaoting Zhang,Xi Li,Jinming Fan,Shengchao Zhao,Junbin Liu,Bin Zhou,Ke Zhang
Background: Hepatocellular carcinoma (HCC), the major form of primary liver cancer, contributes markedly to cancer-related mortality worldwide and remains a serious global health concern, particularly affecting individuals with underlying chronic liver disorders. In hepatocellular carcinoma, insufficient radiofrequency ablation (iRFA) has been reported to drive local tumor relapse and distant spread, possibly by aggravating the immunosuppressive features of the tumor microenvironment. The present work seeks to clarify the underlying pathways driving the development of an immunosuppressive milieu after RFA and to identify potential therapeutic approaches to counteract this process. Methods: An injectable hydrogel composed of quaternized chitosan (QCS) and tannic acid (TA) was constructed to encapsulate verteporfin (VP), a well-established photosensitizer that has been clinically applied for treating neovascular retinal disorders such as age-related macular disease. Beyond its ophthalmologic application, VP has recently been reported to display anti-tumor activity through inhibition of oncogenic regulators such as Yes-associated protein (YAP), indicating its potential utility in cancer therapy. This hydrogel formulation is designed to target residual tumor tissue post-RFA, providing localized delivery and sustained release of VP to enhance anti-tumor immune responses. Results: Our findings identified YAP activation as a critical mediator of immunosuppression in residual tumors following RFA. Pharmacological inhibition of YAP significantly reduced the infiltration of myeloid-derived suppressor cells (MDSCs) and effectively reversed the immunosuppressive microenvironment conditions. Furthermore, the QCS/TA hydrogel enabled sustained local release of VP, resulting in enhanced antitumor immune responses via MDSC suppression. When administered as an adjuvant therapy following suboptimal RFA, the hydrogel markedly inhibited the progression of residual tumors, highlighting its therapeutic potential in improving post-RFA outcomes. Conclusion: Collectively, our data suggest YAP pathway inhibition as a promising immunomodulatory strategy to complement RFA in HCC management. This work demonstrates that the QCS/TA hydrogel-based delivery system can remodel the tumor immune milieu to overcome immunosuppression and delay post-ablation tumor recurrence, supporting its potential as a translational drug delivery strategy.
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