Decoding the Antiperitoneal Fibrosis Axis: SND1-Guided CDC14B mRNA Splicing Inhibits Peritoneal Mesothelial Cell Senescence

Background: Alternative splicing serves as a pivotal RNA processing mechanism that amplifies transcriptomic complexity and proteomic diversity in fibrotic disorders. Emerging evidence underscores the functional significance of RNA-binding protein-regulated splicing variants during fibrogenesis. Staphylococcal nuclease and tudor domain containing 1 gene (SND1) is an RNA-binding protein implicated in extracellular matrix remodeling; however, its regulatory role in peritoneal dialysis (PD)-associated peritoneal fibrosis and the associated splicing circuitry remains mechanistically undefined. Methods: Through analysis of single-cell RNA sequencing data derived from PD patients, we identified SND1 as a hub regulator in fibrogenic niches. Subsequent bulk RNA sequencing with rMATS-mediated alternative splicing profiling deciphered SND1-mediated splicing landscape rewiring. The effects of SND1 on peritoneal mesothelial cell(PMC) senescence and peritoneal fibrosis were detected through a mouse PD model with AAV overexpression or knockdown of SND1 in vivo and in vitro primary PMCs models. Results: SND1 expression was downregulated in PMCs of peritoneal fibrosis models. Bulk RNA-seq showed that knockdown of SND1 in PMCs predominantly dysregulated pathways related to cellular senescence, cell cycle progression, extracellular matrix synthesis, and inflammatory responses. rMATS analysis of bulk RNA-seq data from SND1-knockdown and control cells identified 153 differential alternative splicing events, with exon skipping being the most prevalent type. Notably, cell division cycle 14B(CDC14B) was identified as a key downstream target of SND1. Reduced SND1 expression induced truncation of exon 2 in CDC14B transcripts, leading to diminished full-length CDC14B protein production, cell cycle arrest in PMCs , and subsequent senescence and peritoneal fibrosis progression. In animal studies, AAV-mediated SND1 overexpression attenuated peritoneal fibrosis, whereas SND1 knockdown exacerbated fibrotic severity. Conclusion: SND1 in PMCs suppresses cellular senescence and fibrogenesis by regulating CDC14B alternative splicing. This study reveals a novel mechanism underlying PD-associated peritoneal fibrosis and highlights SND1 as a potential therapeutic target for preventing or mitigating peritoneal fibrosis. Funding: Government Support – Non-U.S.