Evidence map›Paper›PMID 41217483›Full record

ArticleBasic research in cardiology2025

Mixed lineage kinase 3 contributes to myocardial ischemia/reperfusion injury by regulating neutrophil activation.

Zilong Xiao, Xiang Wei, Zhonglei Xie, Qingxing Chen, Ruizhen Chen, Ziqing Yu, Yixiu Liang, Yangang Su, Junbo Ge

Abstract read
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In one paragraph

Article in Basic research in cardiology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. 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

9 authors.

Zilong Xiao *Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Xiang Wei *Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
Zhonglei Xie *Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Qingxing ChenDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Ruizhen ChenDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Ziqing YuDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. yu.ziqing@zs-hospital.sh.cn.
Yixiu LiangDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. liangyixiu@fudan.edu.cn.
Yangang SuDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. su.yangang@zs-hospital.sh.cn.
Junbo GeDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.

Funding

National Natural Science Foundation of China 82100370National Natural Science Foundation of China 82170386
6 · The paper itself

Abstract

Mixed lineage kinase 3 (MLK3), a member of the MAP3K family, is known to participate in cellular stress and inflammatory responses, but its role in neutrophil-mediated myocardial ischemia-reperfusion (I/R) injury remains unclear. In this study, we investigated the function and downstream signaling of MLK3 in neutrophils using genetically modified mouse models with neutrophil-specific MLK3 knockout or overexpression. MLK3 deficiency in neutrophils reduced infarct size, improved cardiac function, and decreased neutrophil infiltration, NET formation, and pro-inflammatory cytokine release following I/R. Transcriptomic profiling revealed that MLK3 promotes the expression of the antimicrobial peptide CRAMP by stabilizing and activating the transcription factor C/EBPβ. Administration of exogenous CRAMP abolished the protective effects of MLK3 deletion, confirming its functional relevance. Furthermore, treatment with CEP-1347, a small-molecule MLK3 inhibitor, attenuated myocardial injury, reduced apoptosis, and limited adverse remodeling in vivo. In acute myocardial infarction (AMI) patients, elevated levels of phosphorylated MLK3 (pMLK3) in circulating neutrophils were associated with increased levels of MPO-DNA, cTnT, and CK-MB, as well as a trend toward higher rates of cardiovascular rehospitalization. These findings identify a neutrophil-intrinsic MLK3-C/EBPβ-CRAMP axis that amplifies myocardial inflammation and injury, and suggest MLK3 as a promising therapeutic target and potential biomarker for ischemic heart disease.

Indexed as

MAP Kinase Kinase KinasesMyocardial InfarctionMyocardial Reperfusion InjuryMyocardiumNeutrophil ActivationNeutrophilsAnimalsApoptosisCCAAT-Enhancer-Binding Protein-betaDisease Models, AnimalHumansMaleMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase Kinase Kinase 11CCAAT-Enhancer-Binding Protein-betaMAP Kinase Kinase KinasesMitogen-Activated Protein Kinase Kinase Kinase 11C/EBPβ signalingCRAMPMixed lineage kinase 3Myocardial ischemia–reperfusion injuryNeutrophils

Identifiers

PMID41217483

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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.