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While SLC25A5 is a well-characterized mitochondrial ADP/ATP transporter, its potential non-canonical roles in cancer remain unclear. This study investigated whether SLC25A5 exerts tumor-suppressive functions in CRC. Using transcriptomic datasets and clinical cohorts, SLC25A5 was significantly downregulated in CRC tissues, and low expression predicted poor survival. Functional restoration inhibited proliferation, EMT, and metastasis in vitro and in vivo. Mechanistically, SLC25A5 associated with EIF3A and promoted EIF3A destabilization via the ubiquitin–proteasome pathway without altering mRNA levels. Cytoplasmic SLC25A5 supported the interaction, EIF3A overexpression partially reversed effects, and reduced PI3K/AKT signaling and AKT activation supported pathway involvement. These findings define an SLC25A5–EIF3A–PI3K/AKT regulatory axis and highlight a mitochondrial carrier’s role in tumor progression.",{"@graph":69,"@context":123},[70,84,106],{"@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/slc25a5-suppresses-colorectal-cancer-growth-and-metastasis-through-regulation-of-the-eif3api3kakt-axis/355798/",{"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/slc25a5-suppresses-colorectal-cancer-growth-and-metastasis-through-regulation-of-the-eif3api3kakt-axis/355798.png","ImageObject",300,407,{"name":92,"@type":93},"Pentious","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",16,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the main question of the study about SLC25A5 in colorectal cancer?","Question",{"text":113,"@type":114},"Whether SLC25A5 has tumor-suppressive, non-canonical roles in colorectal cancer beyond its established mitochondrial ADP/ATP transporter function.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How is SLC25A5 linked to patient outcomes in CRC?",{"text":118,"@type":114},"SLC25A5 is downregulated in CRC tissues, and low expression correlates with poor patient survival.",{"name":120,"@type":111,"acceptedAnswer":121},"What mechanism connects SLC25A5 to CRC progression through EIF3A and PI3K/AKT?",{"text":122,"@type":114},"SLC25A5 associates with EIF3A and promotes EIF3A destabilization via the ubiquitin–proteasome pathway, leading to reduced PI3K/AKT signaling activity; AKT activation partially restores invasive phenotypes.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},355798,1790160462,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},1374404730887,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Article  \nSLC25A5 Suppresses Colorectal Cancer Growth and Metastasis Through Regulation of the EIF3A/PI3K/AKT Axis  \nKe Ying†, Xiang Zhao†, Zhuo Wu, Chi Huang, Qian Wu and Zhongchen Liu *  \nAcademic Editor: Carmine Stolfi  \nReceived: 27 March 2026  \nRevised: 28 April 2026  \nAccepted: 10 May 2026  \nPublished: 13 May 2026  \nCopyright: © 2026 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.  \nSchool of Medicine, Tongji University, Shanghai 200070, China; [yingke159357@163.com](yingke159357@163.com) (K.Y.);  \n[2332316@tongji.edu.cn](2332316@tongji.edu.cn) (X.Z.); [2511275@tongji.edu.cn](2511275@tongji.edu.cn) (Z.W.); [13665546929@163.com](13665546929@163.com) (C.H.);  \n[wqian0405@163.com](wqian0405@163.com) (Q.W.)  \n* Correspondence: [2311206@tongji.edu.cn](2311206@tongji.edu.cn)  \n† These authors contributed equally to this work.  \nAbstract  \nColorectal cancer (CRC) progression is driven by dysregulated signaling networks that promote proliferation and metastasis. While SLC25A5 is a well-characterized mitochondrial ADP/ATP transporter, its potential non-canonical roles in cancer remain unclear. This study investigated whether SLC25A5 exerts tumor-suppressive functions in CRC. Using transcriptomic datasets and clinical cohorts, we found that SLC25A5 is significantly downregulated in CRC tissues, and low expression is associated with poor patient survival. Restoration of SLC25A5 suppressed CRC cell proliferation, epithelial–mesenchymal transition (EMT), and metastasis in vitro and in vivo. Mechanistically, co-immunoprecipitation and protein stability assays suggested an association between SLC25A5 and EIF3A and indicated that SLC25A5 may promote EIF3A destabilization through the ubiquitin–proteasome pathway without altering its mRNA levels. Subcellular fractionation further suggested the presence of a cytoplasmic pool of SLC25A5, providing a potential basis for this interaction. Rescue experiments showed that EIF3A overexpression partially reversed the tumor-suppressive effects of SLC25A5 . In addition, SLC25A5 expression was associated with reduced PI3K/AKT signaling activity, and pharmacological activation of AKT partially restored invasive phenotypes. Collectively, these findings suggest an SLC25A5–EIF3A– PI3K/AKT regulatory axis and reveal a potential non-canonical role for this mitochondrial carrier in tumor progression. This study provides insight into how mitochondrial proteins may influence cytoplasmic signaling pathways in cancer.  \nKeywords: colorectal cancer; SLC25A5; EIF3A; PI3K-AKT pathway; metastasis  \n1. Introduction  \nColorectal cancer remains a major cause of cancer-related mortality worldwide, largely due to its high metastatic potential and resistance to apoptosis [1,2] . Although advances in surgical techniques and targeted therapies have improved patient management, the molecular mechanisms that sustain CRC progression and epithelial–mesenchymal transition are still incompletely understood [3,4] . A deeper elucidation of these regulatory networks is urgently needed to identify more effective prognostic markers and therapeutic targets.  \nMembers of the Solute Carrier Family 25 (SLC25), particularly the mitochondrial adenine nucleotide translocators (ANTs), have traditionally been characterized as essential mediators of ADP/ATP exchange across the inner mitochondrial membrane [5,6] . However, accumulating evidence suggests that certain SLC25 proteins exert context-dependent  \nroles in tumor biology that extend beyond metabolic regulation [7–10] . SLC25A5 (ANT2), in particular, has been implicated in cancer-associated metabolic reprogramming [11], yet its function in colorectal cancer remains ambiguous. Notably, whether SLC25A5 possesses non-canonical, metabolism-independent activities—especially within the cytoplasmic compartment—has not been clearly defined. This gap raises the","cbCaiqCs9QYBi2ey","https://ap.wps.com/l/cbCaiqCs9QYBi2ey","pdf",19200495,21,"English","# Abstract\n# 1. Introduction\n# 2. Results\n## 2.1. SLC25A5 Expression Is Downregulated in CRC and Correlates with Poor Prognosis","[{\"question\":\"What is the main question of the study about SLC25A5 in colorectal cancer?\",\"answer\":\"Whether SLC25A5 has tumor-suppressive, non-canonical roles in colorectal cancer beyond its established mitochondrial ADP/ATP transporter function.\"},{\"question\":\"How is SLC25A5 linked to patient outcomes in CRC?\",\"answer\":\"SLC25A5 is downregulated in CRC tissues, and low expression correlates with poor patient survival.\"},{\"question\":\"What mechanism connects SLC25A5 to CRC progression through EIF3A and PI3K/AKT?\",\"answer\":\"SLC25A5 associates with EIF3A and promotes EIF3A destabilization via the ubiquitin–proteasome pathway, leading to reduced PI3K/AKT signaling activity; AKT activation partially restores invasive phenotypes.\"}]","SLC25A5 Suppresses Colorectal Cancer Growth and Metastasis Through Regulation of the EIF3A/PI3K/AKT Axis | PDF",1790121014,53]