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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PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Weishan Zhuge,Jiayang Kuang,Keke Kuang,Meilin Rao,Dan Jian,Haizhen Lin,Zijun Li,Shaotang Li,Yihu Zheng,Namki Cho,Xiaokun Li,Ri Cui
Background Colorectal cancer (CRC) is among the most prevalent malignancies globally, with its incidence continuing to rise in recent years. Sorafenib, a multi-kinase inhibitor, has shown therapeutic effects in advanced CRC. Usenamine A (UD32-3), a natural compound, is isolated from lichens. However, anti-tumor activity of UD32-3 in CRC and its biological functions in anti-CRC activity of sorafenib remain unknown. Purpose This study aims to elucidate the mechanism underlying anti-CRC effects of UD32-3 and its potential to enhance the therapeutic efficacy of sorafenib. Study design and Methods Immunofluorescence assays were employed to investigate reactive oxygen species (ROS) and autophagy levels. Gene knockdown or overexpression was performed using Lipofectamine 3000 reagent, and relative gene and protein expression levels were evaluated by quantitative real-time PCR (qRT-PCR) and Western blot analyses. Molecular docking analysis was performed to investigate the interaction between UD32-3 and superoxide dismutase 2 (SOD2). Mouse xenograft models were employed to evaluate the effects of combination therapy with UD32-3 and sorafenib. Results UD32-3 exerts anti-CRC activity by inducing ROS-mediated autophagy and inhibiting YAP pathway through targeting SOD2. Knocking down SOD2 sufficiently induced ROS generation and autophagy, and inhibited the YAP pathway, thereby enhancing the anti-CRC activity of UD32-3. Conversely, overexpression of SOD2 yielded opposite results, attenuating these effects. Combined treatment with UD32-3 and sorafenib exerted synergistic anti-tumor activities by activating autophagy and inhibiting YAP signaling pathway. Additionally, YAP inhibitor strengthened anti-CRC activity of UD32-3 and sorafenib by inhibiting SOD2 expression, suggesting autophagy-mediated negative feedback loop between SOD2 and YAP. Conclusions UD32-3 has significant druggable potential, and combination treatment of UD32-3 and sorafenib may serve as an effective therapeutic strategy for patients with certain CRC.
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高影响因子
Postepy Dermatologii i Alergologii
·
2025
·Vol. 42
·期 4
·398-406
·
IF 1.7
Bei Zhao,Yinghua Liu,Xuemei Tang,Shi Cheng
Introduction:The effectiveness of chemotherapy in treating melanoma is limited due to drug resistance. Previous studies have shown that SENP1 (Sentrin/SUMO-specific protease 1) is related to the tumour hypoxic microenvironment, tumorigenesis and metastasis.Aim:This study aimed to investigate its roles in drug resistance of melanoma.Material and methods:Originally, a concentration of 2 µg/ml dacarbazine (DTIC) was employed in the treatment of A375 and M14 cell lines for a duration of 24 h. Subsequently, the cells were transferred to fresh medium and allowed to proliferate until reaching 80% of their maximum density. This treatment cycle was then repeated for a total of 10 days, following which the DTIC concentration was doubled. The establishment of drug-resistant cell lines for both A375 and M14 occurred after 8 months of sustained and continuous treatment. The expression level of SENP1 was monitored monthly using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), with a fold change above 1.5 compared to the untreated condition considered as significant.Results:Finally, the study found that SENP1 was up-regulated by about 2.2-1.7 times in the drug-resistant cells. In addition, overexpression of SENP1 in normal A375 cells improved cell viability against DTIC. The study also found that Yes-associated protein (YAP) could form protein condensates in the cytoplasm while its expression was enhanced by SENP1-mediated deSUMOylation.Conclusions:This study suggests that there is a positive correlation between the ubiquitin-specific protease SENP1 and drug resistance in melanoma. Its up-regulation may lead to changes in the deSUMOylation of YAP, activate the Hippo signalling pathway, and increase the resistance of melanoma to DTIC.
研究领域:
癌症生物学
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分子生物学
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药理学
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细胞生物学
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生物化学
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高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2022
·Vol. 132
·期 4
·297-311
·
IF 3.688
Yu Liao,Kejun Hu,Wangwang Liu,Wei Wang,Huanhuan Qiu,Shumin Pan,Qi Lv,Guanglin Xu
Hepatocellular carcinoma (HCC) is one of the principle causes of cancer-associated death throughout the world. However, the patients with HCC are insensitive to traditional drugs and lack effective therapeutic drugs. Dysregulation of Hippo-Yes-associated protein (YAP) signalling is closely associated with HCC. Bortezomib (BTZ) is mainly used in clinical multiple myeloma. It has recently been confirmed that BTZ could suppress cell proliferation in many different types of cancer. Nevertheless, the precise effects of BTZ on HCC and its possible interactions with the Hippo-YAP signalling pathway in HCC cells remain largely unknown. In this study, HCC cell lines (HepG2 and Huh7) and nude mice with xenograft tumours were used to evaluate the influences of BTZ. Furthermore, we focused on exploring whether BTZ exerts its anti-HCC effect through the Hippo-YAP signalling pathway and aimed to lay a theoretical foundation for BTZ as a potential therapeutic drug for HCC. Herein, our results disclose a new mechanism of BTZ in controlling the cell growth of HCC. BTZ downregulates the level of YAP by promoting LATS1 expression to inhibit the growth of HCC cells, which leads to the phosphorylation of YAP and limits YAP nuclear translocation. In sum, our data confirmed that the Hippo-YAP signalling pathway mediates the anti-HCC effects of BTZ.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Nan Su,Wenhua Lian,Baoding Zhang,Yuan Tian,Linying Li,Yiyu Chen,Xiang Zhi,Taoling Zeng,Qiao Wu,Lanfen Chen,Dawang Zhou,Hong-Rui Wang,Shih-Chin Cheng,Li Li,Xianming Deng
Tumor immune microenvironment greatly influences triple-negative breast cancer (TNBC) progression. Identifying targets to convert “cold” tumors into “hot” tumors holds promise for improving treatment outcomes. Here, we show that high expression of NEDD4, an HECT-type E3 ubiquitin ligase, correlates with poor prognosis and reduced CD8 + T cell infiltration in TNBC patients. NEDD4 depletion in TNBC cells significantly inhibits tumor growth through enhancing CD8 + T cell-mediated cytotoxicity in immunocompetent hosts. Mechanistically, NEDD4 depletion stabilizes β-TrCP, leading to YAP ubiquitination and degradation. Downregulated YAP reprograms the immunosuppressive tumor extracellular matrix (ECM) to increase CD8 + T cell infiltration. Furthermore, a small-molecule inhibitor of NEDD4, XMU-MP-10, exhibits significant in vivo efficacy in inhibiting TNBC tumor growth by enhancing CD8 + T cell infiltration in mouse models. Collectively, our findings suggest that the genetic depletion or pharmacological inhibition of NEDD4 enhances antitumor immune responses via the β-TrCP/YAP/ECM cascades, offering a promising therapeutic strategy for TNBC treatment.
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FOOD AND CHEMICAL TOXICOLOGY
·
2026
·
IF 3.2
Ming Li,Aidana Kablan,Gulziya Toktau,Ashfaq Ahmad,Lun Meng,Ziye Li,Zhaohe Zuo,Songgula Gemingbai,Aknazar Otebay,Arailym Satiyeva,Yingqiu Xie
Inulin as a prebiotic fiber and an industrial additive, has been shown to regulate gut and small intestinal microbiome for health, but non-microbiota-dependent cellular pathways remain unclear. Here we aim to determine how the natural polysaccharide inulin reshapes metabolic stress responses especially in colon cancer cells. In tumor cells treated by inulin, oxidized lipids accumulated in the perimitochondrial region and were accompanied by mitochondrial fragmentation, Golgi dispersion, endoplasmic reticulum (ER) disorganization, lysosomal remodeling, increased mitochondrially encoded cytochrome c oxidase II (MTCO2), and nuclear p21, indicating organelle stress coupled to metabolic reprogramming. Non-malignant cells showed elevated lipid peroxidation but limited necrotic death, consistent with greater metabolic tolerance. YAP/MYC inhibition increased inulin sensitivity. Importantly, ataxia telangiectasia and Rad3-related (ATR) supported stress adaptation, particularly in normal cells. Additionally, inulin decreased nuclear active MYC and YAP and enhanced nuclear androgen receptor (AR). Network pharmacology identified inulin against colon cancer by AR-related hub gene PTGS2 (prostaglandin G/H synthase-2) and validated by a synergistic combination with progesterone. Thus, inulin triggers tumor-selective metabolic stress and disrupts adaptive MYC/YAP, providing a rationale for metabolism-based precision cancer therapy.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Zhu Liang,Keyan Zhang,Hongli Guo,Xujiao Tang,Mingzhu Chen,Jinsong Shi,Jing Yang
Cordycepin (CRD) is an active component derived from Cordyceps militaris , which possesses multiple biological activities and uses in liver disease. However, whether CRD improves liver fibrosis by regulating hepatic stellate cell (HSC) activation has remained unknown. The study aims further to clarify the activities of CRD on liver fibrosis and elucidate the possible mechanism. Our results demonstrated that CRD significantly relieved hepatocyte injury and inhibited HSC activation, alleviating hepatic fibrogenesis in the Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC)-induced mice model. In vitro , CRD exhibited dose-dependent repress effects on HSC proliferation, migration, and pro-fibrotic function in TGF-β1-activated LX-2 and JS-1 cells. The functional enrichment analysis of RNA-seq data indicated that the pathway through which CRD alleviates HSC activation involves cellular senescence and cell cycle-related pathways. Furthermore, it was observed that CRD accumulated the number of senescence-associated a-galactosidase positive cells and the levels of senescence marker p21, and provoked S phase arrest of activated HSC. Remarkably, CRD treatment abolished TGF-β‐induced yes-associated protein (YAP) nuclear translocation that acts upstream of glutaminolysis in activated HSC. On the whole, CRD significantly inhibited glutaminolysis of activated-HSC and induced cell senescence through the YAP signaling pathway, consequently alleviating liver fibrosis, which may be a valuable supplement for treating liver fibrosis.
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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PubMed
高影响因子
STAR Protocols
·
2022
·
IF 0
Jiwen Yang,Minjie Hu,Yongyu Wang
Summary In human pluripotent stem cells (hPSCs), traditional approaches for gene overexpression have low efficiency and are often laborious. Here, we provide a relatively simple protocol for gene overexpression with the Dox-inducible PiggyBac transposon system. We detail the steps for overexpression of FLI1 and/or YAP in H1 embryonic stem cells (H1 ESCs) as an example. Our protocol can be applied to any gene of interest in a variety of hPSCs. For complete details on the use and execution of this protocol, please refer to Quan et al. (2021) .
研究领域:
干细胞生物学
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分子生物学
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基因工程
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DOI
PubMed
CELL CYCLE
·
2023
·
IF 4.3
Huizhi Wang,Yuntao Ding,Qiuming Zhu,Zhengyue Yu,Qi Wang,Aihua Gong,Min Xu
Background Long non-coding RNAs (lncRNAs) have been proved to play a vital role in pancreatic cancer (PC). However, the role of lncRNA FAM83A-AS1 in PC remains unclear. In this study, we explored the biological function and underlying mechanism of FAM83A-AS1 in PC cells.Methods The FAM83A-AS1 expression was assessed via public databases and validated by qRT-PCR. The biofunction and immune cell infiltration of FAM83A-AS1 were analyzed through GO, KEGG, GESA and ssGSEA. The migration, invasion and proliferation abilities of PC cells were examined by Transwell, wound healing, CCK8 and colony formation. The EMT and Hippo pathway markers were evaluated by western blot.Results FAM83A-AS1 expression was higher in PC tissues and cells than normal. Additionally, FAM83A-AS1 was associated with poor prognosis of PC and involved in cadherin binding and immune infiltration. Subsequently, we proved FAM83A-AS1 overexpression enhanced the migration, invasion and proliferation abilities of PC cells, whereas FAM83A-AS1 downregulation inhibited those. Moreover, western blot results showed that FAM83A-AS1 knockdown increased the E-cadherin expression and decreased the expression of N-cadherin, β-catenin, Vimentin, Snail and Slug. On the contrary, FAM83A-AS1 upregulation results in the opposite effects. Besides, FAM83A-AS1 overexpression inhibited the expression of p-YAP, p-MOB1, p-Lats1, SAV1, MST1 and MST2 as well as the results of FAM83A-AS1 knockdown were opposite.Conclusion FAM83A-AS1 promoted EMT of PC cells via Hippo signaling inactivation and may be a potential diagnosis and prognosis target.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2022
·
IF 4.145
Xiaoxue Ma,Yiru Wang,Qi Liu,Baihe Han,Gang Wang,Ruoxi Zhang,Xingtao Huang,Xuedong Wang,Mengyue Yang,Chun Xing,Jingbo Hou,Bo Yu
Vascular calcification (VC) is closely related to higher cardiovascular mortality and morbidity, and vascular smooth muscle cell (VSMC) switching to osteogenic-like cells is crucial for VC. LncRNA LEF1-AS1 promotes atherosclerosis and dental pulp stem cells calcification, while its role in VC remains unknown. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an adipokine regulating bone metabolism. However, the relationship between vaspin and VC is still unclear. We aimed to explore the role of LEF1-AS1 on VSMC osteogenic transition, whether vaspin inhibited LEF1-AS1-mediated osteogenic differentiation of VSMCs, and the responsible mechanism. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis indicated that LEF1-AS1 overexpression significantly upregulated osteogenic marker Runt-related transcription factor-2 (RUNX2) level and downregulated VSMC contractile marker α-smooth muscle actin (α-SMA) level. Alizarin red staining, alkaline phosphatase (ALP) staining, ALP activity assay, and calcium content assay also suggested that LEF1-AS1 overexpression promoted calcium deposition in VSMCs. However, vaspin treatment abolished this phenomenon. Mechanistically, LEF1-AS1 markedly decreased phosphorylated YAP level, while vaspin reversed LEF1-AS1-induced phosphorylated YAP decline. Our results revealed that LEF1-AS1 accelerated the osteogenic differentiation of VSMCs by regulating the Hippo/YAP pathway, while vaspin eliminated the LEF1-AS1-meditated VSMCs osteogenic phenotype switch.
研究领域:
心血管研究
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分子生物学
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细胞生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Nana Long,Youwei Zuo,Jian Li,Renxiu Yao,Xiao Zhang,Hongping Deng
Background Atopic dermatitis (AD) is characterized by epidermal barrier impairment and immune-driven inflammation. Strategies that restore barrier architecture while constraining inflammation are of therapeutic interest. Purpose To evaluate the barrier-reparative and anti-inflammatory effects of β-myrcene (MYR) in experimental atopic dermatitis and to investigate whether ECM–FAK/Src–YAP signaling is associated with these effects. Methods A 2,4-dinitrochlorobenzene (DNCB)-induced murine model of AD-like dermatitis was evaluated by transepidermal water loss (TEWL), histopathology, dermal collagen organization, filaggrin (FLG) immunofluorescence, and circulating inflammatory mediators. Integrated skin transcriptomic and proteomic analyses and public human AD transcriptomic datasets were used to identify MYR-associated pathways. In primary human keratinocytes stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), YAP localization, FAK Tyr397 and Src Tyr416 phosphorylation, YAP/TAZ target genes, barrier markers, and inflammatory outputs were assessed. Peptide 17 was used to examine the contribution of YAP-dependent transcription. Results MYR reduced dermatitis severity and epidermal hyperplasia, lowered TEWL, partially restored FLG immunofluorescence, and preserved dermal collagen organization in DNCB-challenged mice. Multi-omics profiling identified MYR-associated changes in extracellular matrix (ECM)–receptor interaction, focal adhesion, cytoskeletal remodeling, epidermal differentiation, and immune-related programs. In inflamed keratinocytes, MYR was associated with increased FAK and Src phosphorylation, YAP nuclear accumulation, CCN1/CCN2 expression, and barrier-marker expression, together with reduced inflammatory mediator production. Peptide 17 attenuated MYR-associated YAP nuclear accumulation and several downstream transcriptional responses. These findings support the participation of YAP-dependent signaling but do not establish MYR as a direct regulator of FAK, Src, or YAP or demonstrate a strictly linear signaling sequence. Conclusion MYR produced barrier-restorative and anti-inflammatory effects in experimental atopic dermatitis. The results identify ECM–FAK/Src–YAP signaling as a candidate pathway associated with the MYR response, with pharmacological inhibition providing partial functional evidence for a YAP-dependent component. Download: Download high-res image (265KB) Download: Download full-size image
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高影响因子
EXPERIMENTAL CELL RESEARCH
·
2026
·Vol. 462
·期 2
·115168
·
IF 3.5
Yanxia Wang,Yanyan Sun,Peng Shen,Wen Zhang,Wenxuan Pan,Xinchen Zhang,Zhaoxia Xu,Xiumei Guan,Yiying Sun,Min Cheng
MIE-induced WSS exerts a protective effect on vascular endothelial dysfunction. • YAP/TAZ mediate the amelioration of endothelial dysfunction by MIE-induced WSS. • AMPK regulates MIE-induced WSS-mediated protection via inhibiting YAP/TAZ activation. Background Arterial endothelial dysfunction is a critical early pathological change in cardiovascular diseases. Exercise-induced wall shear stress (WSS) exerts protective effects on impaired arterial endothelial function, while the underlying mechanism remains unclear. YAP/TAZ are core mechanotransduction molecules. This study aims to investigate whether YAP/TAZ mediate the ameliorative effect of moderate intensity exercise (MIE)-induced WSS on endothelial dysfunction via AMPK regulation. Methods Lipopolysaccharide (LPS)-injured HUVECs were exposed to MIE-induced WSS using a multicomponent parallel-plate flow chamber system. SiRNA-mediated knockdown of AMPK and YAP was performed to verify the regulatory signaling pathway. In vivo , high-fat diet ApoE −/− mice received MIE intervention to assess the impacts of MIE on endothelial function and YAP expression. Results LPS induced YAP/TAZ activation and endothelial dysfunction, whereas MIE-induced WSS inhibited YAP/TAZ activation and reversed endothelial dysfunction in LPS-treated cells. YAP knockdown strengthened the ameliorative effect of MIE-induced WSS on endothelial dysfunction. Furthermore, AMPK knockdown promoted YAP activation and attenuated the beneficial impact of MIE-induced WSS on endothelial dysfunction. Consistently, MIE intervention reversed high-fat diet-induced impairment of common carotid arterial endothelial function, concurrent with YAP downregulation in vivo . These results indicate that MIE-induced WSS ameliorates endothelial dysfunction via activating AMPK, which in turn inhibits YAP/TAZ. Conclusions This study provides novel insights into the molecular mechanism by which MIE-induced WSS alleviates endothelial dysfunction, and provides a theoretical foundation for the clinical application of MIE as a rehabilitation strategy to improve impaired arterial endothelial function.
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