Integrated stress response genes as novel biomarkers and therapeutic targets in ankylosing spondylitis: a transcriptomic and Mendelian randomization study

Introduction Ankylosing spondylitis (AS) is a chronic inflammatory disorder with poorly defined pathogenic mechanisms. The integrated stress response (ISR), an evolutionarily conserved signaling network, is implicated in AS development. This research endeavored to identify biomarkers for AS, thereby offering novel targets and approaches for therapeutic intervention. Methods Transcriptomic profiling of peripheral blood from AS patients identified differentially expressed genes. Mendelian randomization (MR) was applied to infer causal associations between ISR-related genes and AS susceptibility. Functional enrichment, immune infiltration, and drug prediction analyses were performed, followed by RT–qPCR validation of candidate biomarkers in clinically collected blood samples. Results Both database analyses and clinical validation demonstrated marked downregulation of RORA and FBXO31 and increased expression of MSRB3 in AS. MR analysis substantiated their causal contributions to AS risk. Functional enrichment indicated involvement in olfactory transduction pathways, and strong correlations with immune infiltration, particularly Th1 cells and keratinocytes, were observed. Drug prediction suggested indirubin and pentoxifylline as potential therapeutic agents. Conclusion The findings highlight ISR involvement in AS pathogenesis and identify novel biomarkers and therapeutic targets warranting further investigation.