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Sepsis-induced acute myocardial injury (AMI) is a major contributor to mortality in septic patients, yet its molecular underpinnings remain incompletely understood. While previous studies have largely focused on transcriptional changes, the role of alternative splicing (AS) in septic cardiomyopathy has not been systematically explored.

We employed two widely used murine models of sepsis-cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection-to investigate transcriptomic dysregulation in the heart. Through RNA sequencing, we analyzed both differentially expressed genes (DEGs) and differentially alternative splicing events (DAS), followed by bioinformatic enrichment analysis. Key AS events were validated via RT-PCR and qPCR.

We identified hundreds of sepsis-induced DAS events, with skipped exon (SE) being the most prominent subtype in both CLP and LPS models. Integration of DEG and DAS datasets revealed 127 overlapping genes involved in inflammatory and stress-related pathways, including MAPK, AMPK, and JAK-STAT signaling. Splicing factors such as Cirbp, Rbm3, Cir1 were dysregulated under septic conditions. Validation experiments confirmed model-specific AS events in genes including Per1, Map3k6, and Septin4, which are implicated in circadian regulation, inflammation, and cytoskeletal remodeling, respectively.

This study is the first to comprehensively map AS changes in the septic myocardium using dual models. Our integrative approach reveals that alternative splicing represents a critical and underappreciated regulatory layer in septic cardiac injury, supported by both transcript- and protein-level evidence. These findings broaden the understanding of transcriptomic complexity in sepsis and highlight new molecular targets for therapeutic intervention.