Integrated long-read transcriptomic profiling of peripheral blood from ankylosing spondylitis patients identifies regulatory shifts and core genes associated with programmed cell death.

Ankylosing spondylitis (AS) is a chronic immune-mediated arthritis marked by persistent inflammation and progressive structural damage. Although dysregulation of programmed cell death (PCD) is increasingly recognized in AS pathogenesis, the full spectrum of transcript-level regulation remains unclear. Here, we employed Oxford Nanopore Technologies (ONT) long-read RNA sequencing to comprehensively profile peripheral blood transcriptomes from six AS patients and six matched healthy controls. Our analysis identified 1,088 differentially expressed genes (DEGs) and 1,812 differentially expressed transcripts (DETs), with upregulated transcripts enriched in apoptosis, autophagy, and transcriptional regulation. We further detected 50 transcripts with significant differential usage and 304 alternative splicing events affecting immune- and PCD-related genes, including FCGR2B, TLR2, and STAT5B. Integrative multilayered analysis revealed 26 core genes, such as NAMPT, GATA2, and DDIT3, showing consistent dysregulation at gene, isoform, and splicing levels, highlighting convergent regulatory networks underlying immune imbalance and cell death in AS. These findings provide the first isoform-resolved transcriptomic landscape of PCD regulation in AS, which unveils extensive regulatory complexity and nominates a set of core genes for future mechanistic and therapeutic exploration.