Total parenteral nutrition (TPN) is a life-saving therapy administered to patients who are unable to digest or absorb adequate nutrients via the gastrointestinal tract [1]. Despite the important role of TPN in maintaining the nutritional status of patients, prolonged or inappropriate use of TPN may lead to adverse effects, such as intestinal failure-associated liver disease (IFALD), previously referred to as parenteral nutrition-associated liver disease (or PNALD) [2,3]. IFALD is a disease spectrum that ranges from cholestasis, steatosis, fibrosis, and cirrhosis, which may ultimately lead to liver failure and cause significant morbidity in TPN recipients [2]. However, the exact pathogenesis of IFALD has not been fully clarified.

With the development of RNA-sequencing techniques, bioinformatics data mining of transcriptomic data is a useful tool for identifying novel significant genes involved in the pathogenesis of diseases, providing valuable insights and potential therapeutic targets for further research [4]. However, to date, only one report has investigated the transcriptional regulation of TPN using high-throughput sequencing [5]. This study revealed unique transcriptomic signatures in the liver following TPN administration and identified Hes6 as a key transcriptional regulator in the pathogenesis of IFALD.

In addition to transcriptional regulation, posttranscriptional regulation also plays a key role in regulating gene expression, which is involved in a variety of functional pathways, such as bile metabolism, lipid metabolism, and the inflammatory response. Therefore, exploring the posttranscriptional regulatory features of IFALD will lead to a deeper understanding of the molecular mechanism of IFALD.

Alternative splicing (AS) is an essential process in posttranscriptional mRNA processing and produces various mature mRNAs with different structures and functions. To date, seven basic types of alternative splicing have been identified, including exon skipping, alternative 5′-splice site, alternative 3′-splice site, mutually exclusive exons, intron retention, alternative promoter, and alternative polyadenylation [6]. AS also plays an important role in the pathogenesis of various diseases. For example, the SRSF3-dependent exon inclusion or exclusion of different genes are involved in the liver pathologies of human nonalcoholic fatty liver disease (NAFLD), NASH, and liver cirrhosis [7]. However, the role of AS in IFALD remains unclear.

In the present study, we systematically evaluated the expression of AS events based on the RNA-seq data of liver samples from control and TPN rats. We identified 268 IFALD-regulated AS (RAS) cases and explored the correlation between IFALD-RAS and immune cell infiltration. Finally, we constructed a regulatory network between RNA-binding proteins (RBPs) and IFALD-RAS, which revealed novel regulatory mechanisms underlying IFALD and identified potential therapeutic targets for the treatment of IFALD.