AbstractPyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported.

摘要pyroptosis是gasdermin介导的程序性细胞死亡（PCD）的促炎形式。肿瘤坏死因子-α（TNF-α）是一种炎性细胞因子，一些研究表明TNF-α可以引起细胞的pyroptosis并发挥抗肿瘤作用。然而，TNF-α是否通过诱导pyroptosis对乳腺癌细胞发挥抗肿瘤作用尚未见报道。

In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway.

在这项研究中，为了探讨TNF-α对乳腺癌细胞pyroptosis的影响，我们用TNF-α处理MCF-7细胞，发现TNF-α诱导细胞死亡。。进一步的研究发现，TNF-α在体外对乳腺癌细胞的抗肿瘤作用是通过经典的pyroptosis途径实现的。

In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis.

此外，TNF-α诱导的MCF-7细胞pyroptosis与线粒体功能障碍有关，线粒体膜电位降低，线粒体ROS产生增加。在抑制ROS产生后，TNF-α对NLRP3/Caspase-1/GSDMD途径的激活作用减弱，TNF-α对体外MCF-7细胞生长的抑制作用也降低，进一步证实了ROS参与了TNF-α诱导的pyroptosis。

Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer..

总体而言，我们的研究揭示了TNF-α通过ROS/NLRP3/Caspase-1/GSDMD途径诱导MCF-7细胞发生pyroptosis而发挥抗肿瘤作用的新机制，这可能为乳腺癌的治疗提供新的治疗思路。。

IntroductionBreast cancer (BC) is a common malignant tumor, ranking first in both morbidity and mortality among female malignancies and posing a severe threat to women’s lives and health1. Over the years, researchers have found that cell death is closely related to tumorigenesis and progression of BC.

引言乳腺癌（BC）是一种常见的恶性肿瘤，在女性恶性肿瘤中发病率和死亡率均居首位，对女性的生命和健康构成严重威胁1。多年来，研究人员发现细胞死亡与BC的肿瘤发生和进展密切相关。

Inducing programmed cell death (PCD) has become an important means of BC treatment2,3,4,5,6,7. Apoptosis, a major PCD, has long been considered an important mechanism for preventing the emergence of BC and has been widely studied8. However, since one of the characteristics of tumors is to escape apoptosis, finding other non-apoptotic programmed cell death modalities is essential for BC treatment.Tumor necrosis factor (TNF) was first identified in 1975 from activated macrophages, natural killer cells (NK cells), and T lymphocytes9.

诱导程序性细胞死亡（PCD）已成为BC治疗的重要手段2,3,4,5,6,7。细胞凋亡是一种主要的PCD，长期以来一直被认为是预防BC出现的重要机制，并已被广泛研究8。然而，由于肿瘤的特征之一是逃避细胞凋亡，因此发现其他非凋亡程序性细胞死亡方式对于BC治疗至关重要。。

In 1985, Shalaby named the TNF produced by macrophages TNF-α. As a pleiotropic cytokine, TNF-α plays a vital role in cell survival and death10. Studies have shown that TNF-α has a broad spectrum of cytotoxic effects on various cancer cells, such as colorectal cancer, lung cancer, and sarcoma11. TNF-α has shown a crucial anti-tumor activity in breast cancer cells as well.

1985年，Shalaby将巨噬细胞产生的TNF命名为TNF-α。作为一种多效性细胞因子，TNF-α在细胞存活和死亡中起着至关重要的作用10。研究表明，TNF-α对各种癌细胞具有广泛的细胞毒性作用，如结直肠癌，肺癌和肉瘤11。TNF-α在乳腺癌细胞中也显示出至关重要的抗肿瘤活性。

It is found that high levels of TNF-α are related to a reduced risk of breast cancer progression. Furthermore, TNF-α can inhibit the growth of ER-positive breast cancer cells by influencing cell cycle progression12. Many studies have also confirmed the anti-tumor effect of TNF-α by inducing apoptosis in breast cancer cells.

研究发现，高水平的TNF-α与降低乳腺癌进展的风险有关。此外，TNF-α可通过影响细胞周期进程来抑制ER阳性乳腺癌细胞的生长12。许多研究也证实了TNF-α通过诱导乳腺癌细胞凋亡而具有抗肿瘤作用。

For example, it has been found that TNF-α exerts cytotoxic effects and induces apoptosis in MCF-7 cells. In addition, claudin-1 exerts an anti-apoptotic effect on TNF-α-induced apoptosis in MCF-7 cells13. Gelsolin-mediated ROS production also has important imp.

例如，已经发现TNF-α在MCF-7细胞中发挥细胞毒性作用并诱导细胞凋亡。此外，claudin-1对TNF-α诱导的MCF-7细胞凋亡具有抗凋亡作用13。凝溶胶蛋白介导的ROS产生也具有重要的影响。

Data availability

数据可用性

All data utilized in this study are included in this article.

本文包含了本研究中使用的所有数据。

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Download referencesAcknowledgementsWe would like to thank all those involved in the experiment for their contributions to this study and the experimental environment provided by the laboratory.FundingThis study was supported by grants from the Basic Scientific Research and Business Expenses Project of Heilongjiang Province (2022-KYYWF-0704), the Medical and Health Scientific Research Project of Heilongjiang Province (20220101020737), the Heilongjiang Natural Science Foundation (JQ2021H004).Author informationAuthors and AffiliationsDepartment of Anatomy, Mudanjiang Medical University, Mudanjiang City, 157000, Heilongjiang, ChinaKexin Gao, Yancui Liu, Cheng Sun, Ying Wang, Hongrong Bao & Ping SunDepartment of Nuclear Medicine, Hongqi Hospital affiliated to Mudanjiang Medical University, Mudanjiang City, 157000, Heilongjiang, ChinaGuoyang LiuDepartment of Nuclear Magnetic, the Second People’s Hospital of Mudanjiang City, Mudanjiang City, 157000, Heilongjiang, ChinaJinrui OuAuthorsKexin GaoView author publicationsYou can also search for this author in.

下载参考文献致谢我们要感谢所有参与实验的人，感谢他们对本研究和实验室提供的实验环境所做的贡献。资助本研究得到了黑龙江省基础科学研究和商业支出项目（2022-KYWF-0704），黑龙江省医疗卫生科学研究项目（20220101020737），黑龙江省自然科学基金（JQ2021H004）的资助。作者信息作者和所属单位牡丹江医科大学解剖学系，牡丹江市，157000，黑龙江，中国高可欣，刘燕翠，程孙，王英，鲍红荣，平山，牡丹江医科大学附属红旗医院核医学系，牡丹江市，157000，黑龙江，中国刘国阳牡丹江市第二人民医院，牡丹江市，157000，黑龙江，中国金瑞作者高可欣作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsK.G. and P.S. designed the research; K.G.,Y.L. and C.S. performed the majority of research; G.L. organized the data. Y.W. and J.O. analyzed the data; K.G. and H.B. drafted the manuscript. P.S. supervised the entire study and reviewed the manuscript.All authors read and approved the final manuscript.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献SK。G、 ；K、 G.，Y.L.和C.S.进行了大部分研究；G、 L.整理数据。Y、 W.和J.O.分析了数据；K、 G.和H.B.起草了手稿。P、 美国监督了整个研究并审查了手稿。所有作者都阅读并批准了最终稿件。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleGao, K., Liu, Y., Sun, C. et al. TNF-ɑ induces mitochondrial dysfunction to drive NLRP3/Caspase-1/GSDMD-mediated pyroptosis in MCF-7 cells.

转载和许可本文引用本文Gao，K.，Liu，Y.，Sun，C。等人。TNF-α诱导线粒体功能障碍，以驱动MCF-7细胞中NLRP3/Caspase-1/GSDMD介导的pyroptosis。

Sci Rep 14, 25880 (2024). https://doi.org/10.1038/s41598-024-76997-4Download citationReceived: 31 March 2024Accepted: 18 October 2024Published: 29 October 2024DOI: https://doi.org/10.1038/s41598-024-76997-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsTNF-ɑPyroptosisROSBreast cancer

关键词TNF-αPyroptosisROSBreast cancer