[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-450889-105":59,"doc-detail-450889-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","snapin-facilitates-progression-of-hepatocellular-carcinoma-by-hindering-ferroptosis-through-keap1-degradation-promotion","SNAPIN Facilitates Progression of Hepatocellular Carcinoma by Hindering Ferroptosis Through KEAP1 Degradation Promotion","","Hepatocellular carcinoma (HCC) is a widespread, deadly cancer worldwide. This study reports overexpression of SNAPIN in human HCC tissues and links it to poorer patient prognosis. Cellular experiments show that SNAPIN increases HCC proliferation, while SNAPIN knockdown triggers ferroptosis and SNAPIN overexpression partially counters ferroptosis inducers. Mechanistically, SNAPIN binds directly to KEAP1 and promotes its degradation via autophago-lysosomal pathways, destabilizing KEAP1. As a result, NRF2 and GPX4 rise, lipid peroxidation damage decreases, ferroptosis is suppressed, and HCC progression is facilitated.",{"@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/snapin-facilitates-progression-of-hepatocellular-carcinoma-by-hindering-ferroptosis-through-keap1-degradation-promotion/450889/",{"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/snapin-facilitates-progression-of-hepatocellular-carcinoma-by-hindering-ferroptosis-through-keap1-degradation-promotion/450889.png","ImageObject",300,407,{"name":92,"@type":93},"Fahsai","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What relationship did the study find between SNAPIN expression and HCC prognosis?","Question",{"text":113,"@type":114},"The study observed notable SNAPIN overexpression in human HCC tissues and found it closely linked to patient prognosis, indicating worse outcomes with higher SNAPIN.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does SNAPIN affect ferroptosis in hepatocellular carcinoma cells?",{"text":118,"@type":114},"SNAPIN knockdown induces ferroptosis in HCC cells, while SNAPIN overexpression partially resists the effects of ferroptosis inducers.",{"name":120,"@type":111,"acceptedAnswer":121},"What mechanism explains how SNAPIN suppresses KEAP1 and ferroptosis?",{"text":122,"@type":114},"SNAPIN directly binds KEAP1 and promotes its degradation through the autophago-lysosomal pathway, which undermines KEAP1 stability and leads to upregulation of NRF2 and GPX4, reducing lipid peroxidation and inhibiting ferroptosis.","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},450889,1790816582,{"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,"preview_page_count":4},549768702563,"https://ap-avatar.wpscdn.com/avatar/8000c4aa63b76e948b?x-image-process=image/resize,m_fixed,w_180,h_180&k=1786536092046926083","Cancer Science  \nORIGINAL ARTICLE  OPEN ACCESS   \nSNAPIN Facilitates Progression of Hepatocellular Carcinoma by Hindering Ferroptosis Through KEAP1 Degradation Promotion  \nXuan Liu1  | Weiling Xu1 | Zhen Li1 | Rongqing Li2 | Jin Chen1 | Jianhua Wang1  \n1Department of Gastroenterology, the First People's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, Jiangsu, China | 2Faculty of Medicine, Yangzhou University, Yangzhou, Jiangsu, China  \nCorrespondence: Jin Chen ([chenjin0837@163.com](chenjin0837@163.com)) | Jianhua Wang ([jianhuawang13117@163.com](jianhuawang13117@163.com))  \nReceived: 29 June 2025 | Revised: 9 October 2025 | Accepted: 22 October 2025  \nFunding: This study was funded by the Yancheng City Basic Research Program Guidance Projects (YCBK202212) .  \nKeywords: ferroptosis | GPX4 | hepatocellular carcinoma | KEAP1 | SNAPIN  \nABSTRACT  \nHepatocellular carcinoma (HCC) ranks among the most pervasive forms of cancer worldwide. In our study, we observed a notable overexpression of SNAPIN in human HCC tissues, which was linked closely to patient prognosis. Our experiments demonstrated that SNAPIN enhances the proliferative capacity of HCC cells. The knockdown of SNAPIN induces ferroptosis in HCC cells, whereas its overexpression partially resists the effects offerroptosis inducers. As suggested by the above experimental findings, SNAPIN facilitates HCC progression by hindering HCC cell ferroptosis. Mechanistically, SNAPIN directly binds to KEAP1, facilitating its degradation via the autophago-lysosomal pathway, thereby undermining its stability. Consequently, NRF2 and its downstream target gene, GPX4, are upregulated. These alterations effectively mitigate lipid peroxidation damage, and ultimately impede HCC cell ferroptosis, potentially aiding in the progression of HCC. In conclusion, SNAPIN can negatively regulate the stability of KEAP1 protein, thereby initiating the NRF2/GPX4 pathway to hinder ferroptosis in HCC cells, ultimately facilitating HCC progression. Our results substantiate the pivotal function of SNAPIN in promoting HCC development, and this discovery is expected to provide an innovative therapeutic target for clinically managing HCC.  \n1 | Introduction  \nHepatocellular carcinoma (HCC) has been acknowledged asthe third deadliest contributor to cancer-associated mortalities [1] . Relevant reports indicate that by 2025, the annual cases of newly diagnosed HCC may exceed 1 million in number [2, 3] . Despite recent noteworthy advancements in targeted therapy and immunotherapy for HCC, the post-treatment prognosis is still dismal [4] . Hence, it is paramount to probe deeper into the  \nparticular molecular mechanisms beneath HCC development, with a view to providing innovative, effective targets for its clinical management.  \nAs a recently acknowledged mode of cell death, ferroptosis stands in contrast to other cell death modes, including autophagy, apoptosis, pyroptosis, and necrosis [5, 6] . An abundance of research has discovered the critical function of ferroptosisin tumorigenesis and development, implying its potential as a  \n\n| Abbreviations: 4-HNE, 4-hydroxynonenal; ActD, actinomycin D; CHX, cycloheximide; CQ, chloroquine; DMSO, dimethyl sulfoxide; GPX4, glutathione peroxidase 4; HCC, hepatocellular carcinoma; KEAP1, kelch-like ECH-associated protein 1; MDA, malondialdehyd;malondialdehyde; NRF2, nuclear factor erythroid 2-related factor 2; OsO₄ , osmium tetroxide; ROS, reactive oxygen species.\u003Cbr>Xuan Liu and Weiling Xu contributed equally to this work. |\n| --- |\n| This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\u003Cbr>© 2025 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Associati","cbCainn344APSkzX","https://ap.wps.com/l/cbCainn344APSkzX","pdf",14149266,15,"English","# Introduction\n## Ferroptosis and its relevance to cancer\n## KEAP1/NRF2/GPX4 axis\n## SNAPIN as a SNARE-associated accessory protein","[{\"question\":\"What relationship did the study find between SNAPIN expression and HCC prognosis?\",\"answer\":\"The study observed notable SNAPIN overexpression in human HCC tissues and found it closely linked to patient prognosis, indicating worse outcomes with higher SNAPIN.\"},{\"question\":\"How does SNAPIN affect ferroptosis in hepatocellular carcinoma cells?\",\"answer\":\"SNAPIN knockdown induces ferroptosis in HCC cells, while SNAPIN overexpression partially resists the effects of ferroptosis inducers.\"},{\"question\":\"What mechanism explains how SNAPIN suppresses KEAP1 and ferroptosis?\",\"answer\":\"SNAPIN directly binds KEAP1 and promotes its degradation through the autophago-lysosomal pathway, which undermines KEAP1 stability and leads to upregulation of NRF2 and GPX4, reducing lipid peroxidation and inhibiting ferroptosis.\"}]","SNAPIN Facilitates Progression of Hepatocellular Carcinoma by Hindering Ferroptosis Through KEAP1 Degradation Promotion | PDF",1790734044,38]