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Lztr1 deficiency contributes to the pathogenesis of dilated cardiomyopathy via RAP1/PI3K/AKT-mediated myocardial

Lijun Yang1, Mengqing Wu2, Jiakai Xiang1

  • 1Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

International Journal of Biological Macromolecules
|September 18, 2025
PubMed

Insights

Loss of LZTR1 protein expression in patients is linked to dilated cardiomyopathy (DCM) and heart failure (HF). Mouse models confirm Lztr1 deficiency causes DCM by disrupting mitochondrial function and calcium handling.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • LZTR1, a BTB-Kelch protein, is implicated in cellular processes and myocardial injury.
  • Clinical cases show reduced LZTR1 expression correlates with progressive dilated cardiomyopathy (DCM) and heart failure (HF).
  • The exact molecular mechanisms linking LZTR1 mutations to heart disease are not fully understood.

Purpose of the Study:

  • To investigate the genotype-phenotype relationship of LZTR1 mutations in DCM.
  • To elucidate the pathogenic mechanisms underlying LZTR1 deficiency-induced cardiac dysfunction.

Main Methods:

  • Established cardiac-specific Lztr1 knockdown mouse models using CRISPR-Cas9/AAV9 (CASAAV system).
  • Analyzed cardiac function, mitochondrial integrity, cardiomyocyte apoptosis, and calcium handling in Lztr1-deficient mice.
  • Utilized transcriptomic sequencing to identify affected signaling pathways.

Main Results:

  • Lztr1-deficient mice exhibited DCM pathology, including impaired systolic function, mitochondrial disruption, increased apoptosis, and abnormal calcium handling.
  • Transcriptomic analysis revealed activation of the RAP1/MAPK/AKT signaling pathway in Lztr1-deficient hearts.
  • LZTR1 deficiency leads to disordered calcium homeostasis and apoptosis.

Conclusions:

  • LZTR1 deficiency is a pathogenic mechanism contributing to DCM and heart failure.
  • The RAP1/MAPK/AKT pathway and calcium dysregulation are key mediators of LZTR1-related cardiac dysfunction.
  • LZTR1 represents a potential therapeutic target for DCM.
Keywords:
Calcium (Ca(2+)) homeostasisDilated cardiomyopathy (DCM)LZTR1

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