Toxicology and applied pharmacology最新文献_第3页

Targeting aryl hydrocarbon receptor signaling attenuates hypertension programmed by maternal Di-2-ethylhexylphthalate exposure 靶向芳基烃受体信号可减轻母体暴露于邻苯二甲酸二乙己基酯所致的高血压。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-04-01 Epub Date: 2026-02-03 DOI: 10.1016/j.taap.2026.117751

Chien-Ning Hsu , Hsi-Yun Liu , Chih-Yao Hou , Yu-Wei Chen , Guo-Ping Chang-Chien , Shu-Fen Lin , You-Lin Tain

{"title":"Targeting aryl hydrocarbon receptor signaling attenuates hypertension programmed by maternal Di-2-ethylhexylphthalate exposure","authors":"Chien-Ning Hsu , Hsi-Yun Liu , Chih-Yao Hou , Yu-Wei Chen , Guo-Ping Chang-Chien , Shu-Fen Lin , You-Lin Tain","doi":"10.1016/j.taap.2026.117751","DOIUrl":"10.1016/j.taap.2026.117751","url":null,"abstract":"<div><div>Adverse early-life conditions can predispose offspring to long-term health risks. Phthalate exposure, particularly to di-2-ethylhexylphthalate (DEHP), during pregnancy and lactation has been implicated in programming offspring hypertension via aryl hydrocarbon receptor (AHR) activation, renin–angiotensin system (RAS) dysregulation, nitric oxide (NO) deficiency, and gut microbiota alterations. Using a maternal DEHP exposure rat model, we investigated whether blockade of AHR signaling—directly with the AHR inhibitor CH223191 or indirectly with the indoleamine 2,3-dioxygenase (IDO) inhibitor INCN-024360—prevents offspring hypertension. Pregnant rats received DEHP (10 mg/kg/day) by oral gavage throughout pregnancy and lactation, with or without CH223191 (10 mg/kg/day) or INCN-024360 (50 mg/kg/day). Maternal DEHP exposure induced sustained systolic hypertension in adult male offspring, accompanied by upregulation of renal AHR signaling and RAS components. This effect was attenuated by the IDO inhibitor (approximately 10 mmHg reduction in systolic blood pressure) and more effectively by the AHR inhibitor (approximately 16 mmHg reduction). Mechanistically, the IDO inhibitor reduced asymmetric dimethylarginine (an endogenous nitric oxide synthase inhibitor), renin, and CYP1A1 expression while increasing angiotensin-converting enzyme 2 (ACE2), whereas the AHR inhibitor suppressed renal AHR, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) expression and significantly enhanced short-chain fatty acid receptor expression. Both interventions were associated with distinct alterations in gut microbiota composition. These findings identify AHR as a key mechanistic link between early-life environmental phthalate exposure and programmed hypertension and support early-life AHR blockade as a potential preventive strategy for offspring cardiometabolic–kidney risk.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117751"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protective effect of Florfenicol against DSS-induced ulcerative colitis by inhibiting cellular senescence and reducing inflammation via the AMPK signaling pathway 氟苯尼考通过AMPK信号通路抑制细胞衰老和减少炎症对dss诱导的溃疡性结肠炎的保护作用

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-04-01 Epub Date: 2026-02-08 DOI: 10.1016/j.taap.2026.117755

Wei Lian , Qinran Hou , Jinchan Liu , Cui Chen , Zhiwei Wang , Shujia Song , Min Zhou , Fei He , Xiaobo Wang

{"title":"Protective effect of Florfenicol against DSS-induced ulcerative colitis by inhibiting cellular senescence and reducing inflammation via the AMPK signaling pathway","authors":"Wei Lian , Qinran Hou , Jinchan Liu , Cui Chen , Zhiwei Wang , Shujia Song , Min Zhou , Fei He , Xiaobo Wang","doi":"10.1016/j.taap.2026.117755","DOIUrl":"10.1016/j.taap.2026.117755","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic inflammatory disorder of unclear etiology. Senescence-related signs have been detected in the intestinal tissue of UC patients. Senescence is known to amplify the body's inflammatory response, potentially accelerating UC progression. However, the precise relationship between UC and senescence remains elusive. Florfenicol (FLO) is a broad-spectrum antibiotic characterized by potent antibacterial activity and low toxicity. To date, no studies have reported on the potential of FLO in mitigating intestinal damage and senescence. In this study, we discovered that DSS can induce cellular and colon tissue senescence. Interestingly, we found that FLO can effectively counteract DSS-induced cellular senescence and alleviate DSS-induced ulcerative colitis and colon senescence in C57BL/6j mice. Moreover, we provide strong evidence that FLO effectively inhibits colon senescence and treats DSS-induced colitis by activating the AMPK signaling pathway. Consequently, FLO's anti-senescence properties may represent a novel therapeutic approach for UC management.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117755"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expression of drug transporters in human allogenic transplanted kidneys in acute rejection 急性排斥反应中药物转运体在人同种异体移植肾中的表达。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-23 DOI: 10.1016/j.taap.2026.117735

J. Łapczuk-Romańska , J. Hybiak , K. Piotrowska , M. Marchelek-Myśliwiec , A. Wilk , M. Słojewski , E. Urasińska , M. Droździk

{"title":"Expression of drug transporters in human allogenic transplanted kidneys in acute rejection","authors":"J. Łapczuk-Romańska , J. Hybiak , K. Piotrowska , M. Marchelek-Myśliwiec , A. Wilk , M. Słojewski , E. Urasińska , M. Droździk","doi":"10.1016/j.taap.2026.117735","DOIUrl":"10.1016/j.taap.2026.117735","url":null,"abstract":"<div><div>Kidney drug transporters, primarily located in the basolateral and apical membranes of proximal tubule cells, play a key role in the secretion and reabsorption of drugs and endogenous compounds. Recent studies have demonstrated that kidney diseases can alter transporter expression; however, the expression of these transporters in human transplanted kidneys, with and without rejection, remains unclear. Therefore, the aim of this study was to investigate the mRNA expression (qRT-PCR) and immunolocalization (via immunohistochemistry) of key ABC (ATP-binding cassette) (<em>n</em> = 14) and SLC (solute carriers) (<em>n</em> = 33) transporters in glomeruli and proximal tubule cells from human normal kidney (CTRL, <em>n</em> = 8), non-rejected transplanted kidney (AR-0, <em>n</em> = 7) and transplanted kidney under rejection process (AR-I, n = 8) from patients receiving immunosuppressive drugs. Our study shows that mRNA expression level of <em>SLC22A4</em>, <em>SLC22A6</em>, <em>SLC22A7</em>, <em>SLC22A8</em>, <em>SLC28A1</em>, <em>SLC47A1</em>, <em>SLC22A11</em>, <em>SLC15A2</em>, <em>SLC16A1</em>, <em>ABCC2</em>, <em>ABCC5</em> and <em>ABCC6</em> are statistically significantly downregulated, while <em>SLC22A2</em>, <em>SLCO4A1</em> and <em>ABCB1</em> are statistically upregulated in proximal tubule cells from rejected transplanted kidneys compared to controls. Immunohistochemistry revealed that OAT1, OAT3, OCT2, MATE1, MRP2, MRP6 and P-gp were primarily expressed in proximal tubule cells, with significantly lower protein expression of OAT1, OAT3, P-gp in AR-I and AR-0 biopsies compared to CTRL sections. These preliminary data suggest that the expression profile of kidney transporters may be altered in transplanted kidneys from patients treated with immunosuppressive drugs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117735"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “Elucidating the distinctive regulatory effects and mechanisms of active compounds in Salvia miltiorrhiza Bunge via network pharmacology: Unveiling their roles in the modulation of platelet activation and thrombus formation” [Toxicology and Applied Pharmacology volume 484, March 2024, 116871] “通过网络药理学阐明丹参中活性化合物的独特调节作用和机制：揭示它们在血小板活化和血栓形成调节中的作用”的勘误[毒理学和应用药理学卷484，March 2024, 116871]。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2025-12-04 DOI: 10.1016/j.taap.2025.117668

Ying Zhang , Guang Xin , Qilong Zhou , Xiuxian Yu, Lijuan Feng, Ao Wen, Kun Zhang, Tingyu Wen, Xiaoli Zhou, Qiuling Wu, Hongchen He, Wen Huang

引用次数: 0

EP300 promotes cervical cancer progression through a Wnt/β-catenin–dependent HIF-1α signaling axis EP300通过Wnt/β-catenin依赖性HIF-1α信号轴促进宫颈癌进展。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-19 DOI: 10.1016/j.taap.2026.117718

Yue Zhang , Yongxin Zhang , Ke Wang

{"title":"EP300 promotes cervical cancer progression through a Wnt/β-catenin–dependent HIF-1α signaling axis","authors":"Yue Zhang , Yongxin Zhang , Ke Wang","doi":"10.1016/j.taap.2026.117718","DOIUrl":"10.1016/j.taap.2026.117718","url":null,"abstract":"<div><div>This study aimed to investigate the role of EP300 in cervical cancer progression, focusing on its functional effects related to pyroptosis under Wnt/β-catenin–dependent conditions. In SiHa and HeLa cells, EP300 was silenced using lentiviral-mediated knockdown under hypoxic conditions, and subsequent changes in cell proliferation, inflammatory cytokine secretion, and pyroptosis-related protein expression were evaluated. A subcutaneous HeLa xenograft model was established to examine the in vivo effects. Hypoxia-inducible factor 1-alpha (HIF-1α) expression was also analyzed. The results showed that hypoxia significantly increased the expression levels of EP300, β-catenin, and HIF-1α. EP300 knockdown was associated with decreased Wnt/β-catenin signaling and, under Wnt/β-catenin–dependent conditions, resulted in reduced HIF-1α expression and enhanced pyroptosis-related phenotypes. Activation of Wnt/β-catenin signaling by HLY78 partially reversed these alterations. In vivo, silencing EP300 suppressed tumor growth, decreased Ki67 expression, and increased pyroptosis markers, while activation of the Wnt/β-catenin pathway partially restored proliferation and reduced pyroptosis. Taken together, loss of EP300 function impedes cervical cancer progression by affecting the Wnt/β-catenin signaling axis and inducing concomitant changes in HIF-1α expression. This study provides functional evidence supporting the role of EP300 in the progression of cervical cancer under hypoxic conditions.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117718"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cyclomulberrin represses renal cell carcinoma progression via ferroptosis activation 环黄蛋白通过铁下垂激活抑制肾细胞癌的进展

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-22 DOI: 10.1016/j.taap.2026.117730

Xinyu Yi , Zhixuan Xie , Taian Jin , Ying Ji , Wei Zhu , Dongbiao Lu , Shawky Eman , Shengzhi Liu , Jingkui Tian

{"title":"Cyclomulberrin represses renal cell carcinoma progression via ferroptosis activation","authors":"Xinyu Yi , Zhixuan Xie , Taian Jin , Ying Ji , Wei Zhu , Dongbiao Lu , Shawky Eman , Shengzhi Liu , Jingkui Tian","doi":"10.1016/j.taap.2026.117730","DOIUrl":"10.1016/j.taap.2026.117730","url":null,"abstract":"<div><div>Renal cell carcinoma (RCC) is one of the most common malignancies in the genitourinary system. Cyclomulberrin (CyM), a natural prenylated flavonoid, has shown anti-tumor potential. However, the efficacy and potential mechanisms of this treatment in RCC remain unclear. This study employed MTT, wound-healing, colony-formation, Transwell, and xenograft mouse models to demonstrate that CyM effectively suppresses RCC cell proliferation and migration. To figure out the possible mechanism, untargeted metabolomic and transcriptomic analyses found CyM induced ferroptosis by disrupting the cellular oxidative defense system. Subsequent experiments confirmed key ferroptotic events, including increased lipid peroxidation, accumulation of intracellular Fe<sup>2+</sup>, depletion of glutathione, and mitochondrial dysfunction. Ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversed these events, underscoring the central role of ferroptosis in its anti-tumor activity. In summary, this study first demonstrates that CyM exerts anti-RCC effects by triggering ferroptosis through impairment of the oxidative defense system, induction of mitochondrial damage, and lipid peroxidation. These findings identify a promising therapeutic candidate for RCC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117730"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “Pinocembrin protects against cisplatin-induced liver injury via modulation of oxidative stress, TAK-1 inflammation, and apoptosis” [Toxicology and Applied Pharmacology, Volume 502, September 2025, 117433]. “匹诺曹通过调节氧化应激、TAK-1炎症和细胞凋亡来保护顺铂诱导的肝损伤”[毒理学与应用药理学，vol . 502, September 2025, 117433]。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-18 DOI: 10.1016/j.taap.2026.117719

Samar F. Darwish , Sherif S. Abdel Mageed , Abdulla M.A. Mahmoud , Aya A. El-demerdash , Ahmed S. Doghish , Reem K. Azzam , Roudina E. Mohamed , Engy A. Farouk , Mina Noshy , Marwa M. Shakweer , Ola Elazazy

引用次数: 0

Pre-treatment with sevoflurane alleviates hypoxia-reoxygenation-induced cardiomyocyte damage through PAX8-AS1-targeted miR-145-5p 七氟醚预处理可通过pax8 - as1靶向miR-145-5p减轻缺氧再氧诱导的心肌细胞损伤。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-02 DOI: 10.1016/j.taap.2026.117705

Yan Xu , Xianglong Di , Ye Cai , Shilin Hu

{"title":"Pre-treatment with sevoflurane alleviates hypoxia-reoxygenation-induced cardiomyocyte damage through PAX8-AS1-targeted miR-145-5p","authors":"Yan Xu , Xianglong Di , Ye Cai , Shilin Hu","doi":"10.1016/j.taap.2026.117705","DOIUrl":"10.1016/j.taap.2026.117705","url":null,"abstract":"<div><h3>Objective</h3><div>To explore the regulatory role of the lncRNA PAX8-AS1/miR-145-5p axis in the mitigation of hypoxia-induced damage to oxygenated myocardial cells by sevoflurane (Sev).</div></div><div><h3>Methods</h3><div>A hypoxic-reoxygenation (HR) in vitro model was established by subjecting cells to 4 h of hypoxia followed by 24 h of aeration. An in vivo MI/RI model was established via ischemia-reperfusion. Gene expression was detected using RT-qPCR. Cell proliferation and apoptosis was assessed using CCK8 and flow cytometry. Expression of myocardial injury markers, inflammatory factors, and oxidative stress markers was measured via ELISA. The targeted relationship between genes was validated using dual luciferase reporter assays and RNA immunoprecipitation.</div></div><div><h3>Results</h3><div>Sev can resist the upregulation of PAX8-AS1 and downregulation of miR-145-5p in HR cardiomyocytes or MI/RI myocardial tissue. PAX8-AS1 overexpression attenuates Sev-induced suppression of cardiomyocyte proliferation and apoptosis inhibition following injury Sev pre-treatment reduced the expression of myocardial cell damage markers, inflammatory factors, and oxidative stress markers, but these markers increased after PAX8-AS1 overexpression and decreased after miR-145-5p analogue transfection.</div></div><div><h3>Conclusion</h3><div>Sev can alleviate HR-induced myocardial cell injury by inhibiting PAX8-AS1 and promoting miR-145-5p expression.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117705"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nuclear protein 1 defends against acute pancreatitis by mitigating pancreatic acinar cell ferroptosis through the maintenance of cellular iron homeostasis 核蛋白1通过维持细胞铁稳态来减轻胰腺腺泡细胞铁下垂，从而防御急性胰腺炎。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-17 DOI: 10.1016/j.taap.2026.117720

Xiangtian Zeng , Wenhui Chen , Qixin Dai , Yong He , Xinsong Fu , Jiaxin Liu , Dingwen Zhong , Yonghui Liao

{"title":"Nuclear protein 1 defends against acute pancreatitis by mitigating pancreatic acinar cell ferroptosis through the maintenance of cellular iron homeostasis","authors":"Xiangtian Zeng , Wenhui Chen , Qixin Dai , Yong He , Xinsong Fu , Jiaxin Liu , Dingwen Zhong , Yonghui Liao","doi":"10.1016/j.taap.2026.117720","DOIUrl":"10.1016/j.taap.2026.117720","url":null,"abstract":"<div><div>Acute pancreatitis (AP) is a severe inflammatory condition marked by pancreatic acinar cell death, with ferroptosis emerging as a critical factor in its pathogenesis. The nuclear protein 1 (Nupr1) has been identified as a key regulator of ferroptosis; however, its role in modulating pancreatic acinar cell ferroptosis and its involvement in AP remain unexplored. The objective of this research was to examine whether Nupr1 regulates ferroptosis in pancreatic acinar cells and influences the progression of AP, while elucidating the underlying molecular mechanisms. Nupr1 was significantly upregulated in caerulein-induced AP models. Nupr1 knockdown pancreatic acinar cells exhibited heightened susceptibility to caerulein-induced damage and inflammatory responses, accompanied by elevated levels of ferroptosis. Conversely, overexpression of Nupr1 conferred resistance against caerulein-induced injury, inflammation, and ferroptosis. Inhibition of ferroptosis reversed the sensitivity of Nupr1 knockdown cells to caerulein-induced damage. Further investigations revealed that Nupr1 regulates the expression of lipocalin 2 (Lcn2), thereby maintaining intracellular iron homeostasis. Silencing Lcn2 negated the protective effects of Nupr1 overexpression in pancreatic acinar cells against ferroptosis. In animal models, Nupr1 overexpression significantly attenuated the progression of AP and reduced ferroptotic levels in pancreatic tissues. Collectively, our findings demonstrate that Nupr1 inhibits pancreatic acinar cell ferroptosis by regulating Lcn2-mediated iron homeostasis, thereby mitigating the progression of AP. This research reveals a previously unidentified regulatory mechanism governing acinar cell death in AP and suggests a possible therapeutic target for managing this condition.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117720"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146004031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Histone deacetylase SIRT2 regulates the development and metastasis of tongue cancer via FZD1-mediated Wnt/β-catenin pathway 组蛋白去乙酰化酶SIRT2通过fzd1介导的Wnt/β-catenin通路调控舌癌的发生转移。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-02 DOI: 10.1016/j.taap.2026.117706

Zizheng Lu, Minxiao Lin

{"title":"Histone deacetylase SIRT2 regulates the development and metastasis of tongue cancer via FZD1-mediated Wnt/β-catenin pathway","authors":"Zizheng Lu, Minxiao Lin","doi":"10.1016/j.taap.2026.117706","DOIUrl":"10.1016/j.taap.2026.117706","url":null,"abstract":"<div><div>In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using <em>in vitro</em> and <em>in vivo</em> experiments. Human tongue cancer cells SCC-25, SCC-9, CAL-27, CAL-33 and human oral epithelial cells were cultured for cell line selection. <em>In vitro</em>, SCC-25 cells were manipulated with pcDNA3.1-SIRT2, pcDNA3.1-FZD1, pcDNA3.1-NC, or/and Wnt/β-catenin pathway inhibitor (MSAB) or activator (SKL2001), while CAL-33 cells were treated with siRNA-SIRT2, siRNA-NC or MSAB. The levels of H3K27ac, β-catenin (nuclear, cytoplasmic and total protein), and Wnt1/3a/7a were detected using WB. Based on data from the ENCODE database, the enrichment level of H3K27ac in the FZD1 promoter region was examined by ChIP experiment. Finally, an orthotopic xenograft tumor model in nude mice was constructed for <em>in vivo</em> validation. <em>Re</em>-expression of SIRT2 impaired the proliferative, invasive, and migratory behaviors of tongue cancer cells, while strengthening their apoptosis. Furthermore, SIRT2 decreased H3K27 acetylation, resulting in increased cytoplasmic β-catenin and decreased expression of FZD1, Wnt1/3a/7a, and nuclear β-catenin. FZD1 overexpression or the Wnt/β-catenin pathway activation partially compromised the inhibitory impacts of SIRT2 on the aforementioned behaviors of human tongue cancer cells. The <em>in vivo</em> validation suggested that SIRT2 played a regulatory role in FZD1 expression and Wnt/β-catenin pathway, thereby hindering the growth and metastasis of the orthotopic tongue cancer xenograft model. SIRT2 inhibits the transcriptional expression of FZD1 through H3K27 deacetylation to block the Wnt/β-catenin pathway, consequently suppressing the growth and metastasis of tongue cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117706"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0