{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:09:35Z","timestamp":1771927775318,"version":"3.50.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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>The unfolded protein response (UPR) promotes prostate cancer (PCa) progression, yet its multi-omics landscape and clinical utility remain undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single-cell and bulk transcriptomic datasets, and identified UPR-related genes (UPRRGs) through a combination of differential expression analysis and weighted gene co-expression network analysis (WGCNA), based on which we further developed a consensus UPR-related signature (UPRRS) using a machine learning framework. The UPRRGs were further characterized by functional enrichment, cell-cell communication, and survival analyses. A clinically applicable nomogram integrating UPR-related prognostic genes was constructed for prognostic prediction. Through in silico and in vitro analyses, we validated the clinical relevance between the hub UPRRGs and PCa progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Single-cell analyses revealed elevated UPR activity in prostate epithelial cells, most prominently within the LE-KLK3 subpopulation. These cells exhibited enhanced ligand\u2013receptor interactions in TNF, VEGF and NOTCH signaling axes. A seven-UPRRG signature (including IFRD1, DDIT3, HSPA5) demonstrated robust prognostic performance in the TCGA training set and three external validation cohorts (C-index &amp;gt; 0.82; AUC &amp;gt; 0.80). Multivariate Cox analysis confirmed UPRRS as an independent prognostic factor beyond clinical stage and Gleason score. Mechanistically, the UPRRS-high subgroup displayed an immunosuppressive microenvironment and reduced sensitivity to multiple chemotherapeutics. In vitro knock-down of IFRD1 markedly attenuated PCa cell proliferation and migration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We provide the first systematic single-cell atlas of UPR heterogeneity in PCa and develop a clinically translatable UPRRS prognostic model. IFRD1, a key driver, emerges as a dual diagnostic and therapeutic target, offering both theoretical and experimental foundations for precision stratification and individualized management of PCa.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1744197","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T06:42:08Z","timestamp":1769668928000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics analyses related to unfolded protein response in prostate cancer implicate pro-tumor role of IFRD1"],"prefix":"10.3389","volume":"17","author":[{"given":"Yifeng","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Urology, Affiliated Jintan Hospital of Jiangsu University","place":["Changzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enyao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department 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