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RNA interference was used to knock down CS in three human cancer cell lines (HCT116, HT-1080, HepG2), revealing reduced proliferation, increased apoptosis, lower mitochondrial membrane potentials, elevated reactive oxygen species, and decreased ATP. Transcriptome analyses implicated cell-cycle and apoptosis-related pathways, and targeted verification confirmed mRNA changes in genes linked to apoptotic mechanisms, indicating CS controls diverse cellular processes.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/citrate-synthase-knockdown-suppresses-cell-proliferation-and-induces-apoptosis-in-select-human-cancer-cell-lines/461830/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/citrate-synthase-knockdown-suppresses-cell-proliferation-and-induces-apoptosis-in-select-human-cancer-cell-lines/461830.png","ImageObject",300,407,{"name":92,"@type":93},"Finn","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What happens to cell proliferation and apoptosis after CS knockdown?","Question",{"text":112,"@type":113},"Across HCT116, HT-1080, and HepG2 cells, loss of CS decreased proliferation and increased apoptosis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which cellular bioenergetic and stress indicators change with CS reduction?",{"text":117,"@type":113},"CS knockdown was associated with lower mitochondrial membrane potentials, higher reactive oxygen species production, and reduced ATP levels.",{"name":119,"@type":110,"acceptedAnswer":120},"How were mechanisms investigated beyond measuring cell behaviors?",{"text":121,"@type":113},"The study combined transcriptome analyses to identify pathways related to cell cycle and apoptosis with mRNA verification of specific genes in apoptotic pathways.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},461830,1791097411,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},34359740700684,"https://ap-avatar.wpscdn.com/avatar/1f400023980c374ae676?_k=1777273430885731487","Article  \nCitrate Synthase Knockdown Suppresses Cell Proliferation and Induces Apoptosis in Select Human Cancer Cell Lines  \nXiaoxiao Zhang, Siyu Qu, Huanhuan Zhong, Yulu Yang, Bo Cheng and Yan Zeng *  \nAcademic Editors: Maria Concetta Faniello, Maria Mesuraca and Barbara Quaresima  \nReceived: 10 November 2025  \nRevised: 11 December 2025  \nAccepted: 19 December 2025  \nPublished: 21 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nDepartment of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China;  \n[zhangxx@njau.edu.cn](zhangxx@njau.edu.cn) (X.Z.); [9211010414@stu.njau.edu.cn](9211010414@stu.njau.edu.cn) (S.Q.); [2018116039@njau.edu.cn](2018116039@njau.edu.cn) (H.Z.);  \n[9233310119@stu.njau.edu.cn](9233310119@stu.njau.edu.cn) (Y.Y.); [9201410228@stu.njau.edu.cn](9201410228@stu.njau.edu.cn) (B.C.)  \n* Correspondence: [zengyan@njau.edu.cn](zengyan@njau.edu.cn)  \nAbstract  \nCitrate synthase (CS) catalyzes the first reaction in the tricarboxylic acid (TCA) cycle and is one of the rate-limiting and regulatory enzymes of the TCA cycle. How CS influences human cells beyond its direct roles in carbohydrate metabolism and energy production is poorly understood. In this study, we used RNA interference (RNAi) to knockdown CS expression in three diverse human cancer cell lines, HCT116, HT-1080, and HepG2, and assessed changes in their cellular behaviors. In all three cell lines, the loss of CS led to are duction in cell proliferation, increased apoptosis, lower mitochondrial membrane potentials, higher reactive oxygen species (ROS) production, and reduced ATP levels. We then performed transcriptome analyses in the three cell lines, identified pathways related to the cell cycle and apoptosis that might elucidate the mechanisms underlying those cellular changes, and further verified the mRNA expression changes in specific genes associated with the apoptotic pathways. Taken together, our results suggest that CS regulates a broad spectrum of human cellular processes.  \nKeywords: citrate synthase; the TCA cycle; the cell cycle; apoptosis  \n1. Introduction  \nCS (E.C.2.3.3.1) is an enzyme located in the mitochondrial matrix that catalyzes the formation of citrate from oxaloacetic acid and acetyl coenzyme A [1]. This is the crucial entry point or the first step in the TCA cycle, which, when coupled with the electron transfer chain and oxidative phosphorylation, generates the majority of ATP under aerobic conditions. The TCA cycle also plays a key role in both catabolic and anabolic processes by providing intermediates for the synthesis of sugars, lipids, and amino acids [2] . Biochemically, CSis one of the rate-limiting enzymes of the TCA cycle, but whether and to what extent CS influences cellular processes beyond its functions in carbon and energy metabolism has not been well characterized. In certain species of mice, a CS allele that resulted in a partial loss of CS activity might contribute to age-related hearing loss, even though the exact mechanism is unknown [3–6] . Given that metabolism is intimately associated with tumorigenesis, previous studies had also examined CS’s roles in cancers. Increased CS activity and expression have been reported in human pancreatic cancer, lymphoma, and ovarian cancer [7–9] . But when the RNAi technique was used to investigate the effects of CS knockdown on the behaviors of human cells, including cancer cell lines, conflicting results were obtained. In the human cervical carcinoma cell line HeLa, RNAi against CS enhanced cell proliferation and metastasis [10] . Yet in ovarian cancer cell lines SKOV3 and A2780,  \nCS RNAi reduced cell proliferation, inhibited cell migration, and modestly increased ATP production [9] . In the human glioblastoma cell line SF188, the suppression of CS prevented apoptosis [1","cbCaivD3XL5SGLMP","https://ap.wps.com/l/cbCaivD3XL5SGLMP","pdf",4654516,18,"English","# Abstract\n# Introduction\n# Results\n## RNAi-Mediated Knockdown of CS Expression","[{\"question\":\"What happens to cell proliferation and apoptosis after CS knockdown?\",\"answer\":\"Across HCT116, HT-1080, and HepG2 cells, loss of CS decreased proliferation and increased apoptosis.\"},{\"question\":\"Which cellular bioenergetic and stress indicators change with CS reduction?\",\"answer\":\"CS knockdown was associated with lower mitochondrial membrane potentials, higher reactive oxygen species production, and reduced ATP levels.\"},{\"question\":\"How were mechanisms investigated beyond measuring cell behaviors?\",\"answer\":\"The study combined transcriptome analyses to identify pathways related to cell cycle and apoptosis with mRNA verification of specific genes in apoptotic pathways.\"}]","Citrate Synthase Knockdown Suppresses Cell Proliferation and Induces Apoptosis in Select Human Cancer Cell Lines | PDF",1790762550,45]