2. Academic Validation
  3. Lztr1 deficiency contributes to the pathogenesis of dilated cardiomyopathy via RAP1/PI3K/AKT-mediated myocardial Injury

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

  • Int J Biol Macromol. 2025 Sep 16;329(Pt 1):147723. doi: 10.1016/j.ijbiomac.2025.147723.
Lijun Yang 1,  Mengqing Wu 2,  Jiakai Xiang 1,  Xianrui Hui 3,  Ao Zhang 4,  Xiaoling Guo 4,  Ru Lin 5,  Weize Xu 6,  Qiang Shu 7,  Jinghua Ruan 8
Affiliations

Affiliations

  • 1 Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
  • 2 School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 3 Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China.
  • 4 Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China.
  • 6 Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address: weizexu@zju.edu.cn.
  • 7 Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: shuqiang@zju.edu.cn.
  • 8 Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: jinghuaryan@zju.edu.cn.
PMID: 40967536 DOI: 10.1016/j.ijbiomac.2025.147723
Abstract

LZTR1 is a member of the BTB-Kelch protein family and participates in various cellular processes. Existing studies have reported its association with myocardial injury, which aligns with our clinical case observations, though its precise pathogenic mechanisms remain incompletely understood. Clinical investigations revealed that patient harboring pathogenic LZTR1 mutations displayed markedly diminished LZTR1 protein expression, which was clinically associated with progressive dilated cardiomyopathy (DCM) and decompensated heart failure (HF). To mechanistically interrogate this genotype-phenotype relationship, we established cardiac-specific Lztr1 knockdown mouse models through CRISPR-Cas9/AAV9-mediated gene targeting mutation system (CASAAV). These Lztr1-deficient mice recapitulated human DCM pathology, exhibiting severely compromised systolic function alongside disrupted mitochondrial, elevated cardiomyocyte Apoptosis, and dysregulated Calcium (CA2+) handling kinetics. Subsequently, we validated pathway alterations identified by transcriptomic Sequencing, revealing that Lztr1 deficiency activates the RAP1/MAPK/Akt signaling pathway and leads to the disorder of CA2+ homeostasis and Apoptosis. These findings will facilitate further exploration of LZTR1 as a potential therapeutic target for DCM.

Keywords

Calcium (Ca(2+)) homeostasis; Dilated cardiomyopathy (DCM); LZTR1.

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