Misregulated alternative splicing in endometriosis: a role for aberrant mRNA variants in endometriotic cell growth

Endometriosis is a chronic gynecological disorder marked by the growth of endometrial-like tissue outside the uterus, often leading to pelvic pain, inflammation, and infertility. Despite its global prevalence, diagnosis remains delayed, and effective non-surgical treatments are lacking. While recent transcriptomic studies have identified mRNA transcript changes in ectopic lesions, the contribution of alternative pre-mRNA splicing, a key posttranscriptional regulatory layer, remains largely unknown. In this study, we performed a comprehensive analysis of alternative splicing (AS) events in endometriotic lesions using transcriptomic data. We uncovered distinct alterations in alternative splicing events are associated with endometriosis, highlighting a previously underappreciated layer of gene regulation. Specifically, we discovered that AS events, including exon skipping (SE) and intron retention (IR), were more prevalent than other events, and altered AS events correlated with transcriptomic variation in lesions. We identified two genes, GALNT7 and ZNF28, with significantly reduced exon inclusion in epithelial cells of lesions, potentially resulting in decreased levels of mature transcripts. Functional assays showed that knockdown of GALNT7 and ZNF28, or of critical exons within these genes, increased cellular proliferation, supporting their potential roles as growth‑suppressive genes in endometriotic cells. Together, this study broadens our understanding of transcriptomic dysregulation and highlights misregulated alternative splicing as a potential contributor to endometriotic cell growth and disease progression.