{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:20:42Z","timestamp":1779294042645,"version":"3.51.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["2024B03J0407"],"award-info":[{"award-number":["2024B03J0407"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2013qPCR validation of candidate biomarkers in clinically collected blood samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both database analyses and clinical validation demonstrated marked downregulation of\n                      <jats:italic>RORA<\/jats:italic>\n                      and\n                      <jats:italic>FBXO31<\/jats:italic>\n                      and increased expression of\n                      <jats:italic>MSRB3<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The findings highlight ISR involvement in AS pathogenesis and identify novel biomarkers and therapeutic targets warranting further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1718471","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T06:35:51Z","timestamp":1774506951000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated stress response genes as novel biomarkers and therapeutic targets in ankylosing spondylitis: a transcriptomic and Mendelian randomization study"],"prefix":"10.3389","volume":"17","author":[{"given":"Shuai","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingliang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honghui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengxuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic, Affiliated Hospital of Jiujiang University","place":["Jiujiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaxin","family":"Mei","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College of Guangdong Medical University","place":["Dongguan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chusong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benchao","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41584-021-00625-y","article-title":"Ankylosing spondylitis: an autoimmune or autoinflammatory disease","volume":"17","author":"Mauro","year":"2021","journal-title":"Nat Rev Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113709","article-title":"Ankylosing spondylitis: From pathogenesis to therapy","volume":"145","author":"Wei","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1277959","article-title":"Ankylosing spondylitis and psychiatric disorders in European population: a Mendelian randomization study","volume":"14","author":"Zuo","year":"2023","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.614255","article-title":"Why inhibition of IL-23 lacked efficacy in ankylosing spondylitis","volume":"12","author":"McGonagle","year":"2021","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.747837","article-title":"Targeting the integrated stress response in cancer therapy","volume":"12","author":"Tian","year":"2021","journal-title":"Front Pharmacol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41419-025-07403-8","article-title":"The integrated stress response engages a cell-autonomous, ligand-independent, DR5-driven apoptosis switch","volume":"16","author":"Zappa","year":"2025","journal-title":"Cell Death Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2023.03.029","article-title":"Pros and cons of Mendelian randomization","volume":"119","author":"Zhang","year":"2023","journal-title":"Fertil. 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