[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-376433-105":59,"doc-detail-376433-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","dihydroorotate-dehydrogenase-in-mitochondrial-ferroptosis-and-cancer-therapy","Dihydroorotate Dehydrogenase in Mitochondrial Ferroptosis and Cancer Therapy","","Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since dihydroorotate dehydrogenase (DHODH) was identified in 2021 as a mitochondrial suppressor of ferroptosis, evidence links it to nucleotide metabolism, redox regulation, and cancer progression. This comprehensive review synthesizes mechanistic insights, translational implications, and therapeutic perspectives on DHODH in ferroptosis and cancer, highlighting DHODH’s role in pyrimidine synthesis, ubiquinol regeneration, and tumor resistance, and outlining combination strategies and future directions.",{"@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/dihydroorotate-dehydrogenase-in-mitochondrial-ferroptosis-and-cancer-therapy/376433/",{"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/dihydroorotate-dehydrogenase-in-mitochondrial-ferroptosis-and-cancer-therapy/376433.png","ImageObject",300,407,{"name":92,"@type":93},"PakDamar76","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role does DHODH play in mitochondrial ferroptosis defense?","Question",{"text":113,"@type":114},"DHODH connects pyrimidine synthesis with mitochondrial ferroptosis defense by supporting redox balance and suppressing mitochondrial lipid peroxidation. It is highlighted as a mitochondria-specific protective system that limits propagation of lipid peroxyl radicals.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does DHODH expression affect cancer progression and treatment response?",{"text":118,"@type":114},"Elevated DHODH expression correlates with poor prognosis and is associated with tumor growth, therapy resistance, and immune evasion in multiple cancer types. This suggests DHODH supports survival under therapeutic pressure.",{"name":120,"@type":111,"acceptedAnswer":121},"Why can inhibiting DHODH enhance ferroptosis and cancer therapy?",{"text":122,"@type":114},"Pharmacological DHODH inhibition disrupts pyrimidine synthesis and redox defenses, sensitizing GPX4-low tumors to ferroptosis. Preclinical evidence also supports synergy with chemotherapy, radiotherapy, and immune checkpoint blockade, and nanoparticle delivery may improve efficacy while reducing toxicity.","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},376433,1790315117,{"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},962090893057,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Review  \nDihydroorotate Dehydrogenase in Mitochondrial Ferroptosisand Cancer Therapy  \nJaewang Lee 1,2 and Jong-Lyel Roh 1,3, *  \nAcademic Editor: Dooil Jeoung  \nReceived: 5 November 2025  \nRevised: 24 November 2025  \nAccepted: 26 November 2025  \nPublished: 28 November 2025  \nCitation: Lee, J.; Roh, J.-L. Dihydroorotate Dehydrogenase in Mitochondrial Ferroptosis and Cancer Therapy. Cells 2025, 14, 1889 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells14231889  \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 ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea  \n2 Logsynk, Seoul 06175, Republic of Korea  \n3 Department of Biomedical Science, General Graduate School, CHA University, Pocheon 11160, Republic of Korea  \n* Correspondence: [rohjl@cha.ac.kr or jonglyel.roh@gmail.com](rohjl@cha.ac.kr or jonglyel.roh@gmail.com); Tel.: +82-31-780-2988; Fax: +82-31-780-3449  \nHighlights  \nWhat are the main findings?  \n• DHODH connects pyrimidine synthesis with mitochondrial ferroptosis defense.  \n• Elevated DHODH expression promotes tumor growth and resistance.  \n• DHODH inhibition synergizes with GPX4 blockade to induce ferroptosis.  \nWhat are the implications of the main findings?  \n• Targeting DHODH represents a promising strategy to overcome cancer resistance.  \n• The combination of nanomedicine or immunotherapy enhances therapeutic efficacy.  \n• Integrating DHODH with lipid and iron metabolism pathways may guide precision therapy.  \nAbstract  \nFerroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since the identification of dihydroorotate dehydrogenase (DHODH) as a mitochondrial suppressor of ferroptosis in 2021, increasing evidence has highlighted its role in linking nucleotide metabolism, redox regulation, and tumor progression. We conducted a comprehensive review of publications on DHODH, ferroptosis, and cancer. Relevant studies were analyzed to synthesize mechanistic insights, translational implications, and therapeutic perspectives. DHODH, a flavin-dependent mitochondrial enzyme catalyzing the oxidation of dihydroorotate to orotate, integrates pyrimidine biosynthesis with electron transport chain activity. Beyond its canonical metabolic role, DHODH regenerates ubiquinol (CoQ 10H2 ) to suppress mitochondrial lipid peroxidation and ferroptosis. Elevated DHODH expression in colorectal, hepatocellular, breast, renal, and brain cancers correlates with poor prognosis, therapy resistance, and immune evasion. Pharmacological inhibition of DHODH disrupts pyrimidine synthesis and redox defense, sensitizing GPX4-low tumors to ferroptosis. Preclinical studies demonstrate synergy between DHODH inhibitors and chemotherapy, radiotherapy, or immune checkpoint blockade. Nanoparticle-based delivery systems enhance therapeutic efficacy by simultaneously targeting multiple ferroptosis defense arms while reducing toxicity. DHODH serves as both a metabolic and redox checkpoint in cancer, linking ferroptosis suppression to proliferation and immune escape. Targeting DHODH offers a promising strategy to dismantle cancer resilience, particularly in combination with ferroptosis inducers and immunotherapies. Future research should focus on biomarker-guided stratification, nanomedicine platforms, and clinical translation of DHODH inhibitors.  \nKeywords: dihydroorotate dehydrogenase; ferroptosis; cancer therapy; pyrimidine metabolism; immunotherapy  \n1. Introduction  \nFerroptosis is a regulated form of cell death that is mechanistically distinct from apoptosis, necroptosis, and pyroptosis, and it is primarily driv","cbCaicJWRb9ln5h7","https://ap.wps.com/l/cbCaicJWRb9ln5h7","pdf",1428037,21,"English","# Highlights\n## Main findings and implications\n# Abstract\n# Keywords\n# 1. Introduction","[{\"question\":\"What role does DHODH play in mitochondrial ferroptosis defense?\",\"answer\":\"DHODH connects pyrimidine synthesis with mitochondrial ferroptosis defense by supporting redox balance and suppressing mitochondrial lipid peroxidation. It is highlighted as a mitochondria-specific protective system that limits propagation of lipid peroxyl radicals.\"},{\"question\":\"How does DHODH expression affect cancer progression and treatment response?\",\"answer\":\"Elevated DHODH expression correlates with poor prognosis and is associated with tumor growth, therapy resistance, and immune evasion in multiple cancer types. This suggests DHODH supports survival under therapeutic pressure.\"},{\"question\":\"Why can inhibiting DHODH enhance ferroptosis and cancer therapy?\",\"answer\":\"Pharmacological DHODH inhibition disrupts pyrimidine synthesis and redox defenses, sensitizing GPX4-low tumors to ferroptosis. Preclinical evidence also supports synergy with chemotherapy, radiotherapy, and immune checkpoint blockade, and nanoparticle delivery may improve efficacy while reducing toxicity.\"}]","Dihydroorotate Dehydrogenase in Mitochondrial Ferroptosis and Cancer Therapy | PDF",1790219180,53]