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This study shows that S100P is upregulated in ferroptosis-resistant HCC cells and inhibits ferroptosis. Mechanistically, S100P promotes lysosomal degradation of ACC1 via RAB5C-mediated, P62-dependent selective autophagy, lowering de novo lipid synthesis and increasing ferroptotic sensitivity when S100P is lost. The results define an alternative antiferroptosis pathway and support S100P as a druggable target for HCC.",{"@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/s100p-is-a-ferroptosis-suppressor-to-facilitate-hepatocellular-carcinoma-development-by-rewiring-lipid-metabolism/373999/",{"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/s100p-is-a-ferroptosis-suppressor-to-facilitate-hepatocellular-carcinoma-development-by-rewiring-lipid-metabolism/373999.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-01","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does S100P play in ferroptosis-resistant hepatocellular carcinoma cells?","Question",{"text":112,"@type":113},"S100P is significantly upregulated in ferroptosis-resistant HCC cells and inhibits ferroptosis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does S100P suppress ferroptosis at the molecular level?",{"text":117,"@type":113},"S100P facilitates lysosomal degradation of ACC1 through an RAB5C-dependent, P62-mediated selective autophagy pathway, reducing de novo lipid biosynthesis required for ferroptosis.",{"name":119,"@type":110,"acceptedAnswer":120},"What happens to ferroptosis sensitivity when S100P, RAB5C, or P62 is lost or knocked down?",{"text":121,"@type":113},"Loss of S100P increases ACC1 expression and promotes ferroptotic sensitivity. Knockdown of RAB5C or P62 abolishes S100P-induced ACC1 degradation and restores resistance to ferroptosis.","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},373999,1790331976,{"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":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","Article [https://doi.org/10.1038/s41467-024-55785-8](https://doi.org/10.1038/s41467-024-55785-8)  \nS100Pis a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism  \nReceived: 9 October 2023  \n\n| Accepted: 24 December 2024 |\n| --- |\n| |\n| Check for updates |\n\nMin Yang1,5, Weiwei Cui2,5, Xiaoting Lv1, Gaozhong Xiong1, Caiyu Sun 1, Haocheng Xuan1, Wei Ma3, Xiuling Cui1, Yeping Cheng1, Lihui Han 1  & Bo Chu 4   \nFerroptosis is a newly identified programmed cell death induced by irondriven lipid peroxidation and implicated as a potential approach for tumor treatment. However, emerging evidence indicates that hepatocellular carcinoma (HCC) cells are generally resistant to ferroptosis and the underlying molecular mechanism is poorly understood. Here, our study confirms that S100 calcium binding protein P (S100P), which is significantly up-regulated inferroptosis-resistant HCC cells, efficiently inhibits ferroptosis. Mechanistically, S100P facilitates lysosomal degradation of acetyl-CoA carboxylase alpha (ACC1), which is indispensable forde novo biosynthesis oflipids. Loss ofS100P elevates the expression of ACC1 and promotes ferroptotic sensitivity of HCC cells. S100P-mediated ACC1 degradation relies on RAB5C, which directs ACC1 to lysosome via P62-dependent selective autophagy. Knockdown of RAB5C or P62 abrogates S100P-induced lysosomal degradation of ACC1 and restores resistance of HCC cells to ferroptosis. Our work reveals an alternative antiferroptosis pathway and suggests S100P as a promising druggable target for ferroptosis-related therapy of HCC.  \nHCC is one of the most malignant tumors with high mortality throughout the world. Though the treatment strategies including targeted therapy, immunotherapy, or combination therapy have been significantly improved in the past decade, the intrinsic and acquired drug resistance hampers the therapeutic efficacy, leading to the dismal outcome in most advanced HCC patients. Therefore, clarifying the pathogenesis of HCC and developing novel therapeutic options are urgently needed to ameliorate the morbidity and mortality of HCC patients.  \nFerroptosis, characterized by accumulated peroxidized phospholipids containing long polyunsaturated fatty acid (PUFA-PLs) in an iron-dependent manner, is a newly identified programmed cell death  \nwhich is distinct from apoptosis and necrosis1–4. Although the effect and mechanism of ferroptosis are not yet fully understood, recent studies demonstrate that ferroptosiscan hamper the carcinogenesis in multiple tumors including HCC2,5–18. However, HCC is more resistant to ferroptosis compared with other tumors such as RCC19. The underlying molecular mechanism remains unclear. Therefore, a better understanding of the mechanism of ferroptosis resistance in HCC cells may facilitate therapeutic advancements for ferroptosis-targeted treatment of HCC.  \nS100P is first purified from placenta and is a member of the S100 family of small calcium-binding proteins. S100P is initially produced in the cytoplasm and can also be secreted and act through the receptor  \n1Department of Immunology, Shandong Provincial Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. 2Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China. 3Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. 4Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. 5These authors contributed equally: Min  \nYang, Weiwei Cui. e-mail: [hanlihui@sdu.edu.cn](hanlihui@sdu.edu.cn); [chubo123@sdu.edu.cn](chubo123@sdu.edu.cn)  \nfor advanced glycation end products (RAGE). Although existing literatures suggest that dysregulated expression of S100 proteins is involved in the development and progress","cbCaiuwiY9ubL2iy","https://ap.wps.com/l/cbCaiuwiY9ubL2iy","pdf",3533815,"English","# Introduction\n# S100P is positively correlated with ferroptosis resistance in liver cancers\n# S100P-RAB5C-P62-ACC1 axis drives ferroptosis susceptibility in HCC","[{\"question\":\"What role does S100P play in ferroptosis-resistant hepatocellular carcinoma cells?\",\"answer\":\"S100P is significantly upregulated in ferroptosis-resistant HCC cells and inhibits ferroptosis.\"},{\"question\":\"How does S100P suppress ferroptosis at the molecular level?\",\"answer\":\"S100P facilitates lysosomal degradation of ACC1 through an RAB5C-dependent, P62-mediated selective autophagy pathway, reducing de novo lipid biosynthesis required for ferroptosis.\"},{\"question\":\"What happens to ferroptosis sensitivity when S100P, RAB5C, or P62 is lost or knocked down?\",\"answer\":\"Loss of S100P increases ACC1 expression and promotes ferroptotic sensitivity. Knockdown of RAB5C or P62 abolishes S100P-induced ACC1 degradation and restores resistance to ferroptosis.\"}]","S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism | PDF",1790200999,48]