ArticleScientific reports2020
Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 34 citations in OpenAlex.
- MAP4K4 inhibition enhances the anti-ferroptosis effect of the FTO/YAP/ATF4 axis in doxorubicin-induced cardiotoxicity.Cell biology and toxicology · 2026Article
- Cardioprotective Effects of Simvastatin in Doxorubicin-Induced Acute Cardiomyocyte Injury.International journal of molecular sciences · 2025Article
- Exploring Endocannabinoid System: Unveiling New Roles in Modulating ER Stress.Antioxidants (Basel, Switzerland) · 2024Review
- Navigating cancer therapy induced cardiotoxicity: From pathophysiology to treatment innovations.Advanced drug delivery reviews · 2024Review
- Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases.The Journal of pharmacology and experimental therapeutics · 2024Review
- Striatin plays a major role in angiotensin II-induced cardiomyocyte and cardiac hypertrophy in mice in vivo.Clinical science (London, England : 1979) · 2024Article
- MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1.Cardiovascular diabetology · 2024Article
- Mitochondrial Dynamin-Related Protein Drp1: a New Player in Cardio-oncology.Current oncology reports · 2022Review
- Regulation of Key Immune-Related Genes in the Heart Following Burn Injury.Journal of personalized medicine · 2022Article
- Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity.International journal of molecular sciences · 2022Review
- Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy.ESC heart failure · 2022Article
- MAP4K4 expression in cardiomyocytes: multiple isoforms, multiple phosphorylations and interactions with striatins.The Biochemical journal · 2021Article
- Nanomedicine in Oncocardiology: Contribution and Perspectives of Preclinical Studies.Frontiers in cardiovascular medicine · 2021Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant human platform to guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is an "upstream" member of the MAPK superfamily that is implicated in human cardiac muscle cell death from oxidative stress, based on gene silencing and pharmacological inhibition in hPSC-CMs. A further role for MAP4K4 was proposed in heart muscle cell death triggered by cardiotoxic anti-cancer drugs, given its reported activation in failing human hearts with doxorubicin (DOX) cardiomyopathy, and its activation acutely by DOX in cultured cardiomyocytes. Here, we report successful protection from DOX in two independent hPSC-CM lines, using two potent, highly selective MAP4K4 inhibitors. The MAP4K4 inhibitors enhanced viability and reduced apoptosis at otherwise lethal concentrations of DOX, and preserved cardiomyocyte function, as measured by spontaneous calcium transients, at sub-maximal ones. Notably, in contrast, no intereference was seen in tumor cell killing, caspase activation, or mitochondrial membrane dissipation by DOX, in human cancer cell lines. Thus, MAP4K4 is a plausible, tractable, selective therapeutic target in DOX-induced human heart muscle cell death.
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Registered trials
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.