Comparative study of transcriptomic alterations in sepsis-induced acute liver injury: Deciphering the role of alternative splicing in mouse models.

Background: Sepsis represents a critical health crisis often leading to the failure of multiple organs, with the liver playing a pivotal role in controlling inflammation and defending against systemic infections. The exacerbation of liver damage can escalate sepsis severity, underscoring the necessity to delve into the molecular mechanisms underlying sepsis-induced acute liver injury (ALI). The role of alternative splicing (AS), a complex post-transcriptional mechanism, has been occasionally noted in relation to sepsis across different investigations.

Objective: This research aimed to provide an extensive analysis of gene expression and alternative splicing variants in sepsis-induced ALI using mouse models, thus broadening the understanding of gene-level modulations during sepsis and pinpointing potential therapeutic targets.

Methods: We employed mouse models of ALI induced via both cecal ligation and puncture (CLP) and lipopolysaccharides (LPS). An extensive evaluation was conducted to identify variances in gene expression and the occurrence of alternative splicing variants within the liver tissues of mice afflicted with sepsis.

Results: The results of our study revealed significant alterations in the regulation of genes associated with RNA splicing and numerous pathways related to inflammation following exposure to CLP and LPS. We identified a total of 170 genes exhibiting both differential expression and splicing variations within the groups subjected to CLP and LPS interventions. Four key genes were specifically identified and validated, emphasizing their potential as treatment targets for ALI in sepsis. Among them, Nop58 was found to play a dual role in inflammation regulation, with intron retention linked to pro-inflammatory responses, while its full-length splicing variant exhibited anti-inflammatory properties. Furthermore, our data highlighted the potential role of specific splicing factors, such as Rbm3, Plrg1, and Snip1, in sepsis-induced liver abnormalities.

Conclusion: This study offers a comprehensive insight into the role of AS in sepsis-induced ALI, laying the groundwork for future therapeutic interventions. By demonstrating the functional relevance of specific splicing events, such as those involving Nop58, this work underscores the potential of targeting splicing mechanisms as innovative strategies to mitigate sepsis-induced liver injuries.