Falcarindiol Suppresses Malignant Progression and Induces Ferroptosis in Non-Small Cell Lung Cancer by Regulating JAK/STAT3 Axis

IF 2.8 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-09-03 DOI:10.1002/jbt.70486

Zhenliang Shi, Yimeng Shen, Xin Liu, Shizhao Cheng

{"title":"Falcarindiol Suppresses Malignant Progression and Induces Ferroptosis in Non-Small Cell Lung Cancer by Regulating JAK/STAT3 Axis","authors":"Zhenliang Shi, Yimeng Shen, Xin Liu, Shizhao Cheng","doi":"10.1002/jbt.70486","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n <p>Non-small cell lung cancer (NSCLC) is the most prevalent human malignancy, characterized by high morbidity and mortality rates. Falcarindiol (FAD) has been validated to provide remission in multiple human tumors. However, the function of FAD in NSCLC is unclear. Hence, this research aimed to elucidate the role and potential mechanism of FAD in NSCLC. The toxic effect of FAD on BEAS-2B cells was investigated by cell counting kit-8 (CCK-8) assay. Also, the impact of FAD on NSCLC in vitro models was examined using CCK-8 analysis, western blot analysis, Transwell assay, Fe2+ level determination, immunofluorescence, and transmission electron microscope assays. Furthermore, the mechanism of FAD in NSCLC was assessed with western blot analysis, CCK-8 analysis, Transwell, and Fe2+ level determination. Additionally, the roles of FAD in NSCLC in vivo models were determined using a tumor xenograft model, immunohistochemistry assay, and western blot analysis. FAD concentrations below 160 µM exhibited no significant cytotoxicity toward BEAS-2B cells. FAD reduced NSCLC cell proliferation and invasion functionally, decreased PCNA, ki-67, and N-cadherin protein levels, while FAD increased E-cadherin protein levels. Meanwhile, FAD induced NSCLC cell ferroptosis by increasing Fe2+ and reactive oxygen species levels and decreasing GPX4 and xCT protein levels in NSCLC cells. Also, FAD induced mitochondrial fragmentation in NSCLC. Mechanically, FAD attenuated NSCLC cell proliferation, invasion, and enhanced cell ferroptosis, while RO8191 (activator of JAK/STAT3) reversed these effects. Furthermore, FAD repressed NSCLC cell proliferation in vivo by reducing tumor volume and tumor weight, decreasing ki-67, N-cadherin, GPX4, xCT, p-JAK1, p-JAK2, and p-STAT3 protein levels, and increasing E-cadherin protein levels. FAD attenuated NSCLC proliferation, invasion, and enhanced cell ferroptosis through the inhibition of the JAK/STAT3 signaling pathway.</p>\n </section>\n </div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 9","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biochemical and Molecular Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70486","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Non-small cell lung cancer (NSCLC) is the most prevalent human malignancy, characterized by high morbidity and mortality rates. Falcarindiol (FAD) has been validated to provide remission in multiple human tumors. However, the function of FAD in NSCLC is unclear. Hence, this research aimed to elucidate the role and potential mechanism of FAD in NSCLC. The toxic effect of FAD on BEAS-2B cells was investigated by cell counting kit-8 (CCK-8) assay. Also, the impact of FAD on NSCLC in vitro models was examined using CCK-8 analysis, western blot analysis, Transwell assay, Fe2+ level determination, immunofluorescence, and transmission electron microscope assays. Furthermore, the mechanism of FAD in NSCLC was assessed with western blot analysis, CCK-8 analysis, Transwell, and Fe2+ level determination. Additionally, the roles of FAD in NSCLC in vivo models were determined using a tumor xenograft model, immunohistochemistry assay, and western blot analysis. FAD concentrations below 160 µM exhibited no significant cytotoxicity toward BEAS-2B cells. FAD reduced NSCLC cell proliferation and invasion functionally, decreased PCNA, ki-67, and N-cadherin protein levels, while FAD increased E-cadherin protein levels. Meanwhile, FAD induced NSCLC cell ferroptosis by increasing Fe2+ and reactive oxygen species levels and decreasing GPX4 and xCT protein levels in NSCLC cells. Also, FAD induced mitochondrial fragmentation in NSCLC. Mechanically, FAD attenuated NSCLC cell proliferation, invasion, and enhanced cell ferroptosis, while RO8191 (activator of JAK/STAT3) reversed these effects. Furthermore, FAD repressed NSCLC cell proliferation in vivo by reducing tumor volume and tumor weight, decreasing ki-67, N-cadherin, GPX4, xCT, p-JAK1, p-JAK2, and p-STAT3 protein levels, and increasing E-cadherin protein levels. FAD attenuated NSCLC proliferation, invasion, and enhanced cell ferroptosis through the inhibition of the JAK/STAT3 signaling pathway.

Abstract Image

查看原文本刊更多论文

Falcarindiol通过调控JAK/STAT3轴抑制非小细胞肺癌恶性进展并诱导铁凋亡

非小细胞肺癌（NSCLC）是最常见的人类恶性肿瘤，其特点是高发病率和死亡率。Falcarindiol （FAD）已被证实可缓解多种人类肿瘤。然而，FAD在NSCLC中的作用尚不清楚。因此，本研究旨在阐明FAD在NSCLC中的作用及其潜在机制。采用细胞计数试剂盒-8 （CCK-8）法观察FAD对BEAS-2B细胞的毒性作用。同时，采用CCK-8分析、western blot分析、Transwell实验、Fe2+水平测定、免疫荧光和透射电镜等方法检测FAD对体外NSCLC模型的影响。此外，通过western blot分析、CCK-8分析、Transwell分析和Fe2+水平测定来评估FAD在NSCLC中的作用机制。此外，通过肿瘤异种移植模型、免疫组织化学分析和western blot分析，确定FAD在非小细胞肺癌体内模型中的作用。160µM以下的FAD对BEAS-2B细胞没有明显的细胞毒性。FAD功能性地降低了NSCLC细胞的增殖和侵袭，降低了PCNA、ki-67和N-cadherin蛋白水平，而增加了E-cadherin蛋白水平。同时，FAD通过提高NSCLC细胞中Fe2+和活性氧水平，降低GPX4和xCT蛋白水平诱导NSCLC细胞铁凋亡。此外，FAD诱导非小细胞肺癌的线粒体断裂。机械上，FAD降低了NSCLC细胞的增殖、侵袭并增强了细胞铁凋亡，而RO8191 （JAK/STAT3的激活剂）逆转了这些作用。此外，FAD通过降低肿瘤体积和肿瘤重量，降低ki-67、N-cadherin、GPX4、xCT、p-JAK1、p-JAK2和p-STAT3蛋白水平，以及提高E-cadherin蛋白水平，在体内抑制NSCLC细胞增殖。FAD通过抑制JAK/STAT3信号通路减弱NSCLC的增殖、侵袭和增强细胞铁凋亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Biochemical and Molecular Toxicology 生物-毒理学

CiteScore

5.80

自引率

2.80%

发文量

277

审稿时长

6-12 weeks

期刊介绍： The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.