Myocardial YBX1 is dispensable for cardiac development and function.

The Y-box-binding protein 1 (YBX1) is a DNA- and RNA-binding protein with multifaceted roles in transcriptional, posttranscriptional, and translational regulation. Consequently, YBX1 controls many aspects of cellular function, including proliferation, differentiation, and apoptosis. In recent years, YBX1 emerged as an important player in the cardiovascular system, whose dysregulation underlies many forms of heart disease. Intriguingly, although reducing YBX1 levels in the myocardium confers protection against pathological cardiac remodeling, YBX1 knockdown in the heart also induces cardiac hypertrophy and fibrosis, raising safety concerns about targeting YBX1 therapeutically. Nevertheless, prior YBX1 loss-of-function studies used RNA interference (RNAi), which is susceptible to off-target effects and likely affected multiple cardiac cell types. Therefore, "clean" YBX1 cardiac-specific loss-of-function genetic models are required to delineate YBX1's precise role in the heart. To that end, we constructed both global and cardiomyocyte (CM)-specific Ybx1 knockout (KO) mouse models. Although Ybx1 global KO mice died in utero and exhibited severe cardiac defects, including noncompaction and delayed septal development, Ybx1 cardiomyocytes-specific KO mice (Ybx1cmKO) did not exhibit obvious morphological anomaly or cardiac dysfunction, suggesting that the myocardial YBX1 is dispensable for heart development and function. Although RNA sequencing (RNA-Seq) analysis revealed the upregulation of a few fibrosis-related genes, they did not drive cardiac fibrosis in Ybx1cmKO hearts. Our study provides compelling evidence that deleting YBX1 specifically in CMs would not cause unwanted adverse effects. However, caution is required to ensure the YBX1 ablation is restricted to CMs, as loss of YBX1 in other cell types may lead to cardiac defects.NEW & NOTEWORTHY This study presents a genetic, cardiomyocyte-specific Ybx1 loss-of-function mouse model, addressing limitations of prior RNA interference (RNAi) approaches. Global YBX1 deletion causes embryonic lethality with severe cardiac malformations, whereas cardiomyocyte-specific deletion results in only transient embryonic noncompaction that resolves with normal adult heart structure and function. Cardiac function remained preserved for up to 11 mo, and although fibrosis-related genes were upregulated, no overt fibrotic phenotype was observed, supporting cardiomyocyte-targeted YBX1 reduction as a potentially safe therapeutic strategy.