Evidence map›Paper›PMID 40366325›Full record

ArticleJACC. CardioOncology2025

Mitigation of Doxorubicin Cardiotoxicity With Synergistic miRNA Combinations Identified Using Combinatorial Genetics en masse (CombiGEM).

Yasutomi Higashikuni, Colin Platt, Margaret H Hastings, William C W Chen, Justin R B Guerra, Takeshi Tokuyama, Fuad Gandhi Torizal, Wenhao Liu, Takumi Obana, Abraham L Bayer and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JACC. CardioOncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Risk-guided cardioprotection in cardio-oncology.Nature cardiovascular research · 2026
    Review
  2. Review
  3. Review
  4. Article
  5. Article
  6. Doxorubicin-Induced Cardiotoxicity: A Comprehensive Update.Journal of cardiovascular development and disease · 2025
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Yasutomi HigashikuniDivision of Cardiovascular and Genetic Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan; Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan; Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Colin PlattCardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Margaret H HastingsCardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Stanley and Judith Frankel Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
William C W ChenSynthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Cardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA.
Justin R B GuerraCardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Stanley and Judith Frankel Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Takeshi TokuyamaDivision of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
Fuad Gandhi TorizalDivision of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
Wenhao LiuDepartment of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan.
Takumi ObanaDepartment of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan.
Abraham L BayerDivision of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; Department of Immunology, Tufts University, Boston, Massachusetts, USA.
Hannah WhippleDivision of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Alexandra KuznetsovCardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Ashish YeriCardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Cole TurissiniDivision of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Robert R KitchenCardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Kota ShibayamaDivision of Cardiovascular and Genetic Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
Takayoshi MatsumuraDivision of Cardiovascular and Genetic Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
Norihiko TakedaDepartment of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan.
Hideki UosakiDivision of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
Aarti H AsnaniDivision of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Timothy K LuSynthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Electronic address: timlu@mit.edu.
Anthony RosenzweigCardiovascular Research Center, Division of Cardiology, Corrigan Minehan Heart Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Stanley and Judith Frankel Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, Michigan, USA. Electronic address: anthros@med.umich.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundCardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.

objectivesThe authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.

methodsCombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.

resultsMultiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.

conclusionsWe identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.

Indexed as

cardiac myocytescardiomyopathychemotherapy toxicitycytoprotectiondrug therapyheart failureinnovationpreclinical studysystems biology

Identifiers

PMID40366325
PMCPMC12228136

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Registered trials

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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 OpenQuestion graph.