ArticleCell stem cell2024
CRISPRi/a screens in human iPSC-cardiomyocytes identify glycolytic activation as a druggable target for doxorubicin-induced cardiotoxicity.
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Article in Cell stem cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31citing papers in PubMed
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Who cites it
31 citing papers in PubMed.
- Induced pluripotent stem cells from discovery to translation.Nature medicine · 2026Review
- Review
- Progressive suppression of DNA repair genes with persistent p53 target activation in doxorubicin-treated cardiomyocytes.G3 (Bethesda, Md.) · 2026Article
- Integrative Bioinformatics and Experimental Validation Identify LOX as a Glycolysis-Related Biomarker in Myocardial Ischemia-Reperfusion Injury.Cardiovascular toxicology · 2026Article
- Rewriting the epigenome: CRISPR tools for biological discovery and therapeutics.Current opinion in biomedical engineering · 2026Article
- Cardiotoxicity Induced by Targeted Cancer Therapies: Understanding the Risks and Developing Solutions.Cardiovascular drugs and therapy · 2026Review
- Doxorubicin exposure leads to cardiac fibroblast dysregulation and worsens fibrotic remodeling in the pathological heart.Journal of molecular and cellular cardiology plus · 2026Article
- Association of CA12 with calcification in ER+/HER-2 negative breast cancer.Discover oncology · 2026Article
- Parallel Activation and Interference CRISPR (PAIR) with Sequencing Uncovers DNA Repair Networks Guiding Precision Cell Engineering.bioRxiv : the preprint server for biology · 2026Article
- CRISPR and the Future of Cardiac Disease Therapy: A New Genetic Frontier.International journal of molecular sciences · 2026Review
- Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction.Circulation · 2026Article
- Review
- SC2-3, a Marine Nutrient Glycopeptide fromFoods (Basel, Switzerland) · 2026Article
- Truncating Titin and Lamin A/C Variants in Anthracycline-Induced Cardiomyopathy.JACC. Advances · 2026Article
- A Systemic Selective Modified mRNA Delivery Platform for Preventing Chemotherapy-Induced Cardiotoxicity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Deciphering the regulatory landscape of enhancer RNAs in health and disease.Signal transduction and targeted therapy · 2026Review
- Targeting Cardiac Fibroblast Plasticity for Antifibrotic and Regenerative Therapy in Heart Failure.Cells · 2026Review
- Mitochondrial dysfunction-driven PANoptosis in doxorubicin-induced cardiotoxicity: mechanistic insights and intervention strategies.Frontiers in pharmacology · 2026Review
- Humanized hiPSC Platforms for I/R Injury: Advancing Toward Precision Cardioprotection.Cardiovascular therapeutics · 2026Review
- The mechanisms and therapeutic advances of interactions between breast cancer and cardiovascular diseases.Frontiers in pharmacology · 2026Review
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Authors and funding
20 authors.
Chun LiuStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Department of Physiology and Cancer Center, Milwaukee, WI, USA; Department of Medicine and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: chunliu@mcw.edu.
Mengcheng ShenStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Yanxia LiuDepartment of Bioengineering, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
Amit ManhasStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Shane Rui ZhaoStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Mao ZhangStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Nadjet BelbachirStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Lu RenStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Joe Z ZhangStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Arianne CaudalStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Masataka NishigaStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Dilip ThomasStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Angela ZhangStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Greentstone Biosciences, Palo Alto, CA, USA.
Huaxiao YangDepartment of Biomedical Engineering, University of North Texas, Denton, TX, USA.
Yang ZhouStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Mohamed AmeenStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA.
Nazish SayedStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA; Department of Surgery, Division of Vascular Surgery, Stanford University, Stanford, CA, USA.
June-Wha RheeDepartment of Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Lei S QiDepartment of Bioengineering, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address: slqi@stanford.edu.
Joseph C WuStanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA; Department of Medicine (Division of Cardiology), Stanford, CA, USA. Electronic address: joewu@stanford.edu.
Funding
Project 3 (Mercola)P01HL141084 · NHLBI · STANFORD UNIVERSITY · PI Joseph C. Wu · 2019 to 2026
$21.1MLeveraging innovative technologies in basic and clinical cancer researchT32CA009302 · NCI · STANFORD UNIVERSITY · PI LAURA D ATTARDI, Aaron M Newman · 1985 to 2026
$19.1MHuman iPSCs for Elucidating Intercellular Crosstalk Signaling in Dilated CardiomyopathyR01HL141371 · NHLBI · STANFORD UNIVERSITY · PI WONG, WING H., WU, JOSEPH C. · 2018 to 2025
$6.2MModeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCsR01HL141851 · NHLBI · STANFORD UNIVERSITY · PI WONG, WING H., WU, JOSEPH C. · 2018 to 2025
$5.7MSingle Cell Sequencing of Human iPSC-CM Subtype Identity and FunctionR01HL145676 · NHLBI · STANFORD UNIVERSITY · PI MARK MERCOLA, Joseph C. Wu · 2019 to 2026
$5.1MElucidating Anthracycline-Induced Cell Type-Specific Cardiovascular Toxicity with CRISPRi/a ScreensR01HL150693 · NHLBI · STANFORD UNIVERSITY · PI Ronglih Liao, Joseph C. Wu · 2021 to 2026
$4.1MModeling Susceptibility to Radiation Therapy-induced Cardiotoxicity Using Cell Village iPSCsR01HL171102 · NHLBI · STANFORD UNIVERSITY · PI MARK MERCOLA, Joseph C. Wu · 2024 to 2026
$2.1MHigh resolution dissection of oncogene enhancer networks via CRISPR screening and live-cell imaging.R01CA266470 · NCI · STANFORD UNIVERSITY · PI Lei Stanley Qi · 2022 to 2026
$1.9MUnraveling Proteasome Inhibitor-Induced Cardiovascular Toxicity through Integrative MultiomicsR01HL176822 · NHLBI · STANFORD UNIVERSITY · PI MARK MERCOLA, Joseph C. Wu · 2025 to 2026
$1.4MElucidating anti-angiogenic tyrosine kinase inhibitor-induced vascular dysfunctionR00HL166693 · NHLBI · WASHINGTON UNIVERSITY · PI Mengcheng Shen · 2025 to 2026
$498kA Cas13d-based screening approach to engineer exhaustion-resistant CAR T cellsR21CA270609 · NCI · STANFORD UNIVERSITY · PI QI, LEI STANLEY · 2022 to 2023
$399kParallel Characterization of Genetic Variants in Chemotherapy-Induced Cardiotoxicity Using iPSCsK99HL166773 · NHLBI · STANFORD UNIVERSITY · PI NISHIGA, MASATAKA · 2023 to 2024
$264kAmerican Heart Association-American Stroke Association 19CDA34760019American Heart Association-American Stroke Association 23SCEFIA1156132NCI NIH HHS R01 CA266470NCI NIH HHS R21 CA270609NCI NIH HHS T32 CA009302NHLBI NIH HHS K99 HL166693NHLBI NIH HHS K99 HL166773NHLBI NIH HHS P01 HL141084NHLBI NIH HHS R00 HL166693NHLBI NIH HHS R01 HL141371NHLBI NIH HHS R01 HL141851NHLBI NIH HHS R01 HL145676NHLBI NIH HHS R01 HL150693NHLBI NIH HHS R01 HL171102NHLBI NIH HHS R01 HL176822
Abstract
Doxorubicin is limited in its therapeutic utility due to its life-threatening cardiovascular side effects. Here, we present an integrated drug discovery pipeline combining human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs), CRISPR interference and activation (CRISPRi/a) bidirectional pooled screens, and a small-molecule screening to identify therapeutic targets mitigating doxorubicin-induced cardiotoxicity (DIC) without compromising its oncological effects. The screens revealed several previously unreported candidate genes contributing to DIC, including carbonic anhydrase 12 (CA12). Genetic inhibition of CA12 protected iCMs against DIC by improving cell survival, sarcomere structural integrity, contractile function, and calcium handling. Indisulam, a CA12 antagonist, can effectively attenuate DIC in iCMs, engineered heart tissue, and animal models. Mechanistically, doxorubicin-induced CA12 potentiated a glycolytic activation in cardiomyocytes, contributing to DIC by interfering with cellular metabolism and functions. Collectively, our study provides a roadmap for future drug discovery efforts, potentially leading to more targeted therapies with minimal off-target toxicity.
Indexed as
CardiotoxicityDoxorubicinGlycolysisInduced Pluripotent Stem CellsMyocytes, CardiacAnimalsCarbonic AnhydrasesHumansMiceCarbonic AnhydrasesDoxorubicincarbonic anhydrasecardiomyoctyecardio-oncologyCRISPR screendoxorubicinglycolysisiPSC
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.