IUBMB Life最新文献

{"title":"CircZNF418 Prevents Intervertebral Disc Degeneration by Targeting the HuR/SIRT6 Axis to Protect Against Oxidative Stress-Induced Ferroptosis and Senescence","authors":"Ke Wei,&nbsp;Daming Feng,&nbsp;Dongdong Fan,&nbsp;Junling Chen,&nbsp;Qiwei Du,&nbsp;Jingsong Xue,&nbsp;Guibin Zhong,&nbsp;Jianwei Chen","doi":"10.1002/iub.70049","DOIUrl":"10.1002/iub.70049","url":null,"abstract":"<div>\u0000 \u0000 <p>Intervertebral disc degeneration (IVDD) is a common degenerative disorder affecting the spine. Ferroptosis and cellular senescence are key pathological features driving IVDD progression, but the mechanisms involved in their regulation remain incompletely understood. While circular RNAs (circRNAs) have been implicated in nucleus pulposus cells (NPCs) function, the specific role of circZNF418 in IVDD has not been explored. In this study, we aimed to investigate the function and mechanism of circZNF418 in IVDD, focusing on its impact on oxidative stress-induced ferroptosis and senescence in NPCs. NPCs were treated with tert-butyl hydroperoxide to mimic oxidative stress during IVDD progression. The levels of malondialdehyde (MDA) and glutathione (GSH) were quantified using commercial kits, and senescence was assessed using SA-β-gal staining. Gene and protein expression was analyzed using qPCR, Western blotting, immunofluorescence, and immunohistochemistry. RNA pull-down and immunoprecipitation were used to examine interactions among circZNF418, HuR, and SIRT6. circZNF418 levels were found to be lower in degenerative nucleus pulposus tissues, associated with increased ferroptosis and cellular senescence. circZNF418 expression declined in response to oxidative stress and was correlated with increased NPC senescence and ferroptosis. Overexpression of circZNF418 protected NPCs from oxidative damage, while its knockdown exacerbated senescence and ferroptosis. Silencing of SIRT6 partially reversed the protective effects of circZNF418 overexpression. Additionally, both circZNF418 and SIRT6 were shown to bind to HuR, with circZNF418 promoting SIRT6 expression, which was reversed by HuR silencing. The findings indicate that circZNF418 regulates NPC senescence and ferroptosis by upregulating SIRT6. A novel signaling pathway, the novel circZNF418/HuR/SIRT6 axis, was identified, showing its potential in IVDD therapy, while circZNF418 was identified as a potential target, thus providing new diagnostic biomarkers and the development of effective treatments for IVDD.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 8","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabidiol Suppresses EMT in Pancreatic Cancer via Inhibition of MALAT1 lncRNA and PI3K/Akt/mTOR Signaling Pathway","authors":"Na Young Kim,&nbsp;Young Yun Jung,&nbsp;Jae-Young Um,&nbsp;Kwang Seok Ahn","doi":"10.1002/iub.70042","DOIUrl":"10.1002/iub.70042","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive metastasis and poor response to chemotherapy, largely driven by epithelial–mesenchymal transition (EMT) and chemokine signaling. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has shown anticancer potential, yet its mechanisms in EMT regulation remain underexplored in PDAC. In this study, we demonstrate that CBD significantly suppresses the expression of CXCR4/CXCR7 and matrix metalloproteinases (MMP-2/9), leading to reduced migration and invasion of MIA PaCa-2, PANC-1, and AsPC-1 cells. Moreover, CBD reversed CXCL12-induced EMT by downregulating mesenchymal markers and restoring epithelial markers. Mechanistically, CBD inhibited the expression of the long non-coding RNA <i>MALAT1</i>, a known EMT regulator, and antagonized its pro-invasive effects. Overexpression of <i>MALAT1</i> activated the PI3K/Akt/mTOR pathway and enhanced EMT-related protein expression, all of which were effectively reversed by CBD. Furthermore, the combination of CBD and gemcitabine exhibited synergistic inhibition of <i>MALAT1</i>, EMT markers, and PI3K/Akt/mTOR signaling without inducing cytotoxicity, suggesting a therapeutic advantage. Collectively, these findings reveal a novel mechanism through which CBD impedes PDAC metastasis and underscore its promise as a complementary agent in chemotherapy regimens.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 8","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Synergic Inhibition of Wilforlide A With Cisplatin in Lung Cancer Is Mediated Through Caspase-3 and NFκB Signaling","authors":"Zhonglu Peng,&nbsp;Xiang Xiao,&nbsp;Xinyi Lu,&nbsp;Dong Cao,&nbsp;Huilong Fang,&nbsp;Zhiying Yang,&nbsp;Dongyang He","doi":"10.1002/iub.70043","DOIUrl":"10.1002/iub.70043","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung cancer is a malignant disease in the respiratory system and accounts for hundreds of thousands of deaths each year. Cisplatin is the first-line drug in the clinic for lung cancer. However, drug resistance and side effects are becoming a big problem. Combination therapy is a good strategy to deal with this issue and has exhibited better efficacy. Wilforlide A (WA), a natural herb extract, has anti-inflammatory activity and increases the efficacy of docetaxel in prostate cancer. Accordingly, this study aims to investigate the role of WA in lung cancer. Here, WA was shown to inhibit proliferation and invasion in lung cancer but induced apoptosis. Combined administration of WA with cisplatin (WA/cisplatin) showed better efficacy to inhibit proliferation and to induce apoptosis. The level of total ROS was increased by WA, and WA/cisplatin treatment exhibited higher ROS production. Furthermore, WA was shown to induce the activity of the caspase-3-mediated signaling pathway, and this activation was enforced by WA/cisplatin. In addition, the critical members in NFκB signaling pathway, such as p65, IKK, and HDAC, were decreased by WA when IκB was increased reversely. In conclusion, this study suggests that WA is a promising molecule harboring the activity to inhibit the progression of lung cancer and to increase the efficacy of cisplatin.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 8","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RING Finger Protein 4 (RNF4) Reduces Nonalcoholic Fatty Liver Disease Accumulation by Promoting the SUMOylation of HIF-2α and Regulating the PPARα Signaling Pathway","authors":"Li Yang,&nbsp;Qing Ni,&nbsp;Yan He,&nbsp;Shijie Liu,&nbsp;Lulu Gan,&nbsp;Anni Dai,&nbsp;Yang Hu,&nbsp;Qian Liu,&nbsp;Xueling Yang,&nbsp;Jiqian Li,&nbsp;Yi Tao,&nbsp;Yunyu Li,&nbsp;Mingyue Xu","doi":"10.1002/iub.70047","DOIUrl":"10.1002/iub.70047","url":null,"abstract":"<div>\u0000 \u0000 <p>RING finger protein 4 (RNF4) acts as a SUMO-targeted ubiquitin ligase, principally regulating protein stability and playing a crucial role in liver injury, inflammatory, and cholestatic diseases. In spite of this, it is unclear how it contributes to nonalcoholic fatty liver disease (NAFLD). The rat model of NAFLD was constructed by feeding a high-fat diet (HFD), and HepG2 cells were treated with 1 mmol/L oleic acid (OA) for 24 h. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to measure the expression of associated genes and proteins. Oil red O staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and hematoxylin–eosin (HE) staining were used to assess damage to HepG2 cells and rat liver tissues. RNF4 expression is reduced in NAFLD. Overexpression of RNF4 in HepG2 cells reduced triglyceride (TG) and total cholesterol (TC) levels and increased high density lipoprotein cholesterol (HDL-C) levels. In addition, overexpression of RNF4 suppressed lipogenic genes liver X receptor alpha (LXRα), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1), and cytochrome P4A11 (Cyp4a11), inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and cell apoptosis; it also inhibited lipid accumulation in vivo and improved liver tissue pathology, thereby mitigating NAFLD progression. Mechanistically, RNF4 promotes SUMOylation and ubiquitin-mediated degradation of hypoxia inducible factor-2 alpha (HIF-2α), thereby enhancing peroxisome proliferator-activated receptor alpha (PPARα) expression, reducing lipid accumulation, inflammation, and cell apoptosis, ultimately alleviating NAFLD development. Our research indicates that RNF4 may be a novel therapeutic target for NAFLD.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 8","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircROBO2 Orchestrates Osimertinib Resistance Through miR-625-5p/PDGFB-Mediated MAPK Activation in Non-Small Cell Lung Cancer","authors":"Miao He,&nbsp;Jiang-ying Cai,&nbsp;Ying-ying Wang,&nbsp;Xin Ma,&nbsp;Chong-ge You,&nbsp;Hong-wei Gao","doi":"10.1002/iub.70045","DOIUrl":"10.1002/iub.70045","url":null,"abstract":"<div>\u0000 \u0000 <p>The emergence of acquired resistance to osimertinib represents a formidable therapeutic challenge in the management of non-small cell lung cancer (NSCLC). While circular RNAs (circRNAs) have been increasingly recognized as crucial modulators of chemotherapeutic resistance, their specific involvement in osimertinib resistance mechanisms remains poorly elucidated. We established osimertinib-resistant NSCLC cell lines (HCC4006OR) through prolonged drug exposure and conducted comprehensive transcriptome sequencing to identify differentially expressed circRNAs. The molecular characteristics and functional implications of circROBO2 were systematically investigated utilizing an array of cellular and molecular biological methodologies. Advanced molecular dynamics simulations were implemented to elucidate the potential molecular interactions between PDGFB and osimertinib. We identified circROBO2 as significantly upregulated in osimertinib-resistant HCC4006OR cells. Functional studies revealed that circROBO2 enhances cell survival, proliferation, and invasion while suppressing apoptosis under osimertinib treatment. Mechanistically, circROBO2 functions as a molecular sponge for miR-625-5p, resulting in elevated PDGFB expression and subsequent activation of the MAPK pathway, particularly the RAF/MEK/ERK cascade. Targeting this pathway through circROBO2 knockdown or miR-625-5p overexpression partially restored osimertinib sensitivity in resistant cells. Molecular dynamics simulations suggested potential direct interactions between PDGFB and osimertinib, providing additional insights into the resistance mechanism. Our study identifies a novel circROBO2/miR-625-5p/PDGFB regulatory axis in osimertinib resistance and positions circROBO2 as a potential therapeutic target and biomarker for NSCLC treatment.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYC-Mediated Osseous Regeneration via BMSCs/PRP/β-TCP/PCL Bioprinted Constructs: Rapid Defect Rehabilitation and Preliminary Clinical Efficacy Evaluation","authors":"Dinghao Luo,&nbsp;Zhaoyang Ran,&nbsp;Junxiang Wu,&nbsp;Lei Wang,&nbsp;Wen Wu,&nbsp;Kai Xie,&nbsp;Liang Deng,&nbsp;Yongqiang Hao","doi":"10.1002/iub.70036","DOIUrl":"10.1002/iub.70036","url":null,"abstract":"<div>\u0000 \u0000 <p>Bone defects present significant clinical challenges due to their morphological heterogeneity and structural complexity, necessitating regenerative strategies that integrate structural adaptability, biomechanical stability, and osteogenic potential. In this study, a bioengineered construct composed of bone marrow mesenchymal stem cells (BMSCs), platelet-rich plasma (PRP), polycaprolactone (PCL), and β-tricalcium phosphate (β-TCP) was fabricated using 3D bioprinting. In vitro assays assessed osteoprogenitor cell proliferation (CCK-8), migration (Transwell), differentiation (ALP staining), and endothelial tubulogenesis (Matrigel assay). In vivo bone regeneration was evaluated using a rabbit femoral condyle defect model, with histomorphometric analysis (Masson and COL-1 staining). Mechanistic insights were explored via RNA sequencing and western blot analysis. Clinical validation included pre- and postoperative assessments of visual analog scale (VAS) scores and computed tomography (CT) imaging in patients with osseous defects. The bioprinted constructs significantly enhanced BMSCs proliferation (<i>p</i> &lt; 0.01), migration (<i>p</i> &lt; 0.0001), and ALP activity (<i>p</i> &lt; 0.0001), while promoting endothelial tubulogenesis (<i>p</i> &lt; 0.01). In vivo, the BMSCs/PRP/PCL/β-TCP group exhibited greater Masson staining and collagen type I expression than controls at 2 weeks, 1 month, and 6 months postoperatively. Clinically, VAS scores significantly decreased (3.33 ± 1.63 pre-op vs. 0.50 ± 0.84 post-op, <i>p</i> = 0.005) with no severe complications. PRP concentration-dependently upregulated MYC expression (mRNA: <i>p</i> &lt; 0.0001; protein: <i>p</i> &lt; 0.0001), while MYC knockdown abrogated PRP-induced ALP and RUNX2 expression, confirming MYC's regulatory role in osteogenesis. In conclusion, BMSCs/PRP/PCL/β-TCP bioprinted constructs enhance MYC-mediated bone regeneration, demonstrating promising clinical potential for bone defect repair.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The IUBMB Focused Meeting on Aminoacyl-tRNA Synthetases 2023","authors":"Patrick O'Donoghue,&nbsp;Ilka U. Heinemann","doi":"10.1002/iub.70041","DOIUrl":"10.1002/iub.70041","url":null,"abstract":"<div>\u0000 \u0000 <p>By ligating amino acids to their cognate transfer RNAs (tRNAs), the aminoacyl-tRNA synthetases (AARSs) establish the genetic code in all living cells. This special issue of <i>IUBMB Life</i> is dedicated to the IUBMB Focused Meeting on AARSs in 2023 and includes 12 original research articles and reviews that demonstrate some of the significant advances in AARS biology that were featured at the meeting. The articles focus on the role of AARS variants in human disease, molecular evolution of AARSs, synthetic biology applications involving AARSs, and the roles of AARSs and tRNAs in regulating protein synthesis. Together these studies reveal an expanded understanding of the function of AARSs in diverse cells and organisms and the application of these discoveries to biotechnology and medicine.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deacetylase Inhibitor Trichostatin A Promotes the Proliferation of Epithelial Cells and Suppresses Glycolytic Activity of Fibroblasts in the Kidney","authors":"Marina I. Buyan,&nbsp;Irina B. Pevzner,&nbsp;Andrey I. Buyan,&nbsp;Ljubava D. Zorova,&nbsp;Dmitry B. Zorov,&nbsp;Nadezda V. Andrianova,&nbsp;Egor Y. Plotnikov","doi":"10.1002/iub.70044","DOIUrl":"10.1002/iub.70044","url":null,"abstract":"<div>\u0000 \u0000 <p>Undesirable tissue fibroblast activation after injury is still an unresolved problem for many organs, including the kidney. Kidney fibroblasts and tubular epithelial cells demonstrate significant differences in gene expression profiles, including metabolism-related genes. As a result, these cell types exhibit differences in the energy metabolism that could be the basis of targeted therapy for fibrosis. Among other deacetylase inhibition is considered a therapeutic approach that could simultaneously promote tissue regeneration and suppress the development of fibrosis, but their relation to bioenergetics has not been considered before. In this study, we aimed to compare the influence of the HDAC inhibitor trichostatin A (TSA) on renal tubular epithelial cells and kidney fibroblasts. We analyzed resemblance and differences in TSA effects on the proliferative activity of the cells and investigated the molecular mechanisms responsible for these effects; e.g., we focused on the activity of signaling pathways associated with cell viability (Akt/mTOR/p70^S6). We found that TSA increased the proliferation rate of epithelial cells, while it tended to decrease the growth rate of fibroblasts. Furthermore, the amount of phosphorylated forms of kinases Akt and P70^S6 increased in epithelial cells after incubation with TSA, indicating the activation of the Akt/mTOR/p70^S6 signaling pathway, while decreasing its activity in fibroblast cells. Since there are differences in the bioenergetics between fibroblasts and epithelial cells, we investigated the impact of TSA on the glycolytic activity of both cell types. Indeed, we showed that TSA reduced the activity of glycolytic processes in fibroblast cells. The observed changes indicate a positive effect of TSA on regenerative versus fibrotic processes in the kidney by reducing the growth and metabolic activity of fibroblasts and activating the proliferation of epithelial cells.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of Initiated Cell Line Derived From NIH3T3 Fibroblasts","authors":"Myeong-Han Ro,&nbsp;Taehyun Park,&nbsp;SungHee Hwang,&nbsp;Hye-Gyo Kim,&nbsp;Michael Lee,&nbsp;Misu Lee","doi":"10.1002/iub.70039","DOIUrl":"10.1002/iub.70039","url":null,"abstract":"<div>\u0000 \u0000 <p>Autophagy plays contrasting roles depending on the stage of cellular transformation. However, although advanced tumor cell models are abundant, cell lines at the initiation stage of transformation are very limited. Therefore, the development of initiated cell lines—cells that have acquired early genetic alterations but not yet completed the multistep transformation process —is crucial for the development of anticancer drugs targeting autophagy. In this study, we successfully established a new initiated cell line (Foci #3) from foci formed in the in vitro two-stage cell transformation assay with NIH3T3 fibroblast cells. Foci #3 cells retained typical features of epithelial morphology, similar to its parental untransformed NIH3T3 cells. However, unlike NIH3T3 cells, where many dead cells were found during the long-term culture of 40 days, few dead cells were observed in Foci #3 cells. Particularly, the sensitivity of Foci #3 cells to the autophagy inhibitor CQ was higher than that of NIH3T3 cells and similar to that of Bhas 42 cells, the most commonly used initiated cell line. Moreover, Foci #3 cells maintained a higher level of autophagic flux than NIH3T3 cells throughout the extended culture period, indicating acquisition of the characteristic of dependence on autophagy for survival, which is typical of transformed cells. Importantly, qPCR analysis of epithelial–mesenchymal transition gene expression revealed that the Foci #3 cell line exhibited characteristics of both non-tumorigenic and tumorigenic states. Whole-genome sequencing analysis revealed that among the 17 genes with exon mutations in the Foci #3 cells, four were tumor suppressors and eight were involved in oncogenesis. Additionally, the Foci #3 cell line exhibited the loss of copy number variations in several tumor suppressors. Together, our results suggest that the newly developed Foci #3 cell line may be an efficient tool for elucidating the role of autophagy in the early stages of transformation.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Treatment Strategy for Lung Cancer With HDAC and Wnt/β-Catenin Pathway Inhibitors","authors":"Elif Erturk,&nbsp;Oguzhan Akgun,&nbsp;Yaren Yildiz,&nbsp;Gonca Tuna,&nbsp;Ferda Ari","doi":"10.1002/iub.70037","DOIUrl":"10.1002/iub.70037","url":null,"abstract":"<p>Lung cancer is a type of cancer with high morbidity and mortality rates worldwide. The overall survival rate of lung cancer patients is low due to a lack of therapeutic options. Recently, the combination of histone deacetylase (HDAC) inhibitors with anti-cancer agents offers a promising therapeutic strategy for cancer treatment. Repurposing these drug combinations is important to evaluate their preventive effect on the epithelial mesenchymal transition (EMT) phenotype, which plays a critical role in tumor progression and metastasis. In this study, the changes that the combination of the HDAC inhibitor Valproic acid (VPA) and Wnt/β-Catenin pathway inhibitor Niclosamide (Niclo) may cause in cytotoxicity, apoptosis, cell cycle, and EMT mechanisms in lung cancer cell lines (A549 and H1299) were examined. According to the results, the combination of VPA + Niclo significantly reduced cell viability in lung cancer cells compared to the use of Niclo alone. ELISA and Western blot analyses revealed that the combination of VPA + Niclo significantly enhanced the total acetylation of Histone H3 compared to the use of VPA alone. It was also found that the combination treatment induced apoptosis by increasing the activity of Caspase 3/7 and Annexin-V and significantly increased the percentage of apoptotic cells by causing depolarization of mitochondria. After cell cycle analysis, the combination treatment increased G1 phase retention in A549 cells, while G1-G2/M phase retention increased in H1299 cells. Wound healing and transwell migration assay results showed that the VPA + Niclo combination treatment inhibited cell migration in lung cancer cells. According to Western blot and PCR results, after VPA + Niclo treatment, the increase in E-Cadherin levels and the decrease in <i>β</i>-Catenin, Fibronectin, Vimentin, and N-Cadherin levels at both protein and gene levels indicated that combination therapy may be useful in preventing the EMT process in lung cancer cells. As a result of the analyses, it was seen that VPA + Niclo combination therapy could play a critical role in preventing the acquisition of the mesenchymal phenotype, reducing cell migration and invasion ability, and preventing tumor cell survival and resistance to apoptosis. In conclusion, it was determined that VPA + Niclo combination treatment shows anticancer activity in lung cancer cells and is a promising approach that may have a synergistic effect in inhibiting EMT.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}