ArticleInflammation2025
MLKL-Mediated Necroptosis Predominantly Contributes to Immune-Associated Myocardial Damage.
Article in Inflammation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
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Who cites it
6 citing papers in PubMed.
- Suppression of Calpain Attenuates Coxsackievirus B3-Induced Myocarditis by Regulating RIPK1/RIPK3/MLKL Pathway.Journal of cardiovascular translational research · 2026Article
- Interaction between Regulated Cell Death Pathways and Core Cellular Processes: Unraveling the Molecular Mechanisms of Cardiotoxicity of Antitumor Drugs.Current treatment options in oncology · 2026Review
- Metabolic syndrome necroptosis: disease implications and therapeutic targeting.Journal of physiology and biochemistry · 2026Review
- Targeting MLKL-Driven Necroptosis: A Therapeutic Target in Inflammation and Host Defense.Biomolecules · 2026Review
- Immune checkpoint inhibition and heart injury: molecular mechanisms and clinical challenges.ESC heart failure · 2026Review
- Mitochondrial Permeability Transition Pore: The Cardiovascular Disease's Molecular Achilles Heel.Biomedicines · 2025Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Activated T cells and macrophages play a critical role in immune-associated myocarditis. However, the molecular and cellular mechanisms driving cardiomyocyte damage by immune cells remain poorly understood. In this study, we co-cultured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with activated human peripheral blood mononuclear cells (aPBMCs) to recapitulate myocardial infiltration of immune cells. Our results demonstrated that aPBMCs induced hiPSC-CMs death in a dose- and time-dependent manner. Transcriptome analysis revealed the activation of several death pathways, including pyroptosis, apoptosis and necroptosis. The time course of immunofluorescence staining of key proteins related to different death pathways demonstrated that necroptosis was the earliest activated pathway. Pharmacological blockade of necroptosis by targeting mixed lineage kinase domain-like protein (MLKL), receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein RIPK1 kinase 3 (RIPK3) protected hiPSC-CMs against injury induced by aPBMCs, while inhibitors of pyroptosis and apoptosis showed no protective effect. Moreover, MLKL knockdown in hiPSC-CMs prevented cell death due to aPBMCs challenge. Additionally, we validated the cardioprotective effects of blocking necroptosis in a mouse model of immune checkpoint inhibitors (ICIs)-related myocarditis using a combination of long-term anti-programmed cell death 1 (PD- 1) and anti-cytotoxic T-lymphocyte antigen- 4 (CTLA- 4) antibodies. ICIs led to elevation of myocardial injury markers in serum and activated immune cells infiltration. Furthermore, in vivo administration of a MLKL inhibitor prevented ICIs-induced myocardial injury. In conclusion, our findings suggested that MLKL-mediated necroptosis predominantly contributed to cardiomyocyte death resulting from activated immune cells. Suppressing necroptosis may be an effective therapeutic approach against myocardial damage in myocarditis.
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