The role of serine/arginine-rich splicing factors in cardiovascular diseases

Alternative splicing is a fundamental post-transcriptional mechanism that contributes to cardiovascular development, homeostasis, and disease. Serine/arginine-rich splicing factors (SRSFs), a conserved family of 12 RNA-binding proteins, regulate splice-site selection and other RNA-processing events through their RNA-recognition motifs and arginine/serine-rich domains. Growing evidence implicates SRSF dysregulation in congenital heart disease, cardiac hypertrophy and heart failure, ischemic injury, vascular remodeling, inflammatory myocardial injury, and cardiovascular aging. In this review, we summarize the structural characteristics, cardiovascular expression patterns, and physiological functions of SRSFs, and discuss their context-dependent roles across cardiovascular diseases. We further examine regulatory mechanisms involving phosphorylation, target-specific RNA processing, interactions with other cardiac splicing regulators, and non-coding RNAs. Finally, we evaluate emerging small-molecule and gene- or RNA-based strategies targeting SRSFs and highlight major barriers to translation, including target specificity, delivery, causal validation, and safety. These advances provide a framework for defining disease-relevant SRSF networks and prioritizing mechanistically supported therapeutic targets in cardiovascular disease.