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

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 murine models through CRISPR-Cas9/AAV9-mediated gene targeting. These Lztr1-deficient mice recapitulated human DCM pathology, exhibiting severely compromised systolic function alongside disrupted mitochondrial, elevated cardiomyocyte apoptosis and dysregulated 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.