Systematic Dysregulation of Immune-Related Alternative Polyadenylation in Systemic Lupus Erythematosus Contributes to Patient Stratification

Background: Alternative polyadenylation (APA) is a common post-transcriptional gene regulatory mechanism. Although dysregulated APA is associated with various human diseases, its role in Systemic Lupus Erythematosus (SLE) remains largely unexplored. We systematically characterized immune-related APA alterations in SLE and investigated their potential for clinically useful patient stratification. Methods: We integrated RNA-seq data from multiple SLE cohorts involving peripheral blood samples and quantified APA using the DaPars2. We developed a scoring framework to identify key immune-related APA events (ImmAPA) and their utility for grouping SLE patients. And we used the Connectivity Map to explore potential differences in drug response across ImmAPA groups and examined these associations in an independent SLE cohort treated with an immunosuppressive drug. Results: SLE patients exhibited a recurrent trend in lengthening of the 3 ' untranslated region (3 ' UTR) across cohorts. Twenty key APA regulators showed enhanced associations with these changes in SLE patients. The ImmAPA score can group patients into ImmAPA-high and ImmAPA-low subtypes, reflects activation states, and correlates with disease severity. The ImmAPA score captured complementary transcriptomic variation compared with interferon signature. CMap analysis predicted drugs that could reverse these APA changes, and was supported by follow-up analysis. Conclusions: Our study reveals a recurrent and widespread shift toward 3 ' UTR lengthening in SLE at peripheral blood transcriptome level. The ImmAPA framework provides a new perspective for SLE patient stratification and offers insights into precision therapeutic strategies in SLE.