{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:12:51Z","timestamp":1788772371431,"version":"build-2803163510"},"reference-count":60,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":249,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis\u2010induced acute respiratory distress syndrome (ARDS) is a fatal inflammatory lung injury. The integrated stress response (ISR) may play stage\u2010dependent roles in lung injury, but its clinical relevance in sepsis\u2010induced ARDS remains unclear. We aimed to identify ISR\u2010related biomarkers and explore their potential mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Public transcriptomic datasets of sepsis\u2010induced ARDS were analyzed. Peripheral blood mononuclear cell (PBMC) single\u2010cell RNA sequencing (scRNA\u2010seq) was used to define key immune cell populations and intercellular communication. Differential expression analyses combined with machine learning were applied to screen ISR\u2010associated biomarkers, and a nomogram was developed as an exploratory tool for ARDS risk stratification. Biomarker expression was validated in a cecal ligation and puncture (CLP)\u2010based rat model representing early sepsis and ARDS\u2010like lung injury. Lung injury was assessed by light and electron microscopy, histological scoring, lung wet\/dry weight ratio, and BALF total protein measurement. Gene expression was quantified by qPCR and protein levels by Western blotting. Functional enrichment, immune infiltration, and trajectory analyses were performed to investigate underlying pathways and immune dynamics. The biomarkers were further validated in an independent external dataset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nuclear factor erythroid 2\u2010like 2 (NFE2L2) and ZFP36L1 were identified as potential ISR\u2010associated biomarkers in sepsis\u2010induced ARDS, and the two\u2010gene nomogram showed good predictive performance. In vivo, peripheral blood Tnf and Il6 mRNA expression increased after CLP, while rats with ARDS\u2010like lung injury exhibited marked lung injury and reduced tight junction markers. Nfe2l2 and Zfp36l1 mRNA levels were elevated in early sepsis but decreased in established ARDS\u2010like lung injury, while their protein levels were generally reduced in established ARDS\u2010like lung injury compared with early sepsis. Canonical ISR activation markers, including the p\u2010eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1)\/total eIF2\u03b1 ratio and Atf4, Ddit3\/Chop, and Ppp1r15\u2009a\/Gadd34 expression, progressively increased from early sepsis to ARDS\u2010like lung injury. Enrichment analyses implicated multiple ISR\u2010related pathways. Immune infiltration analysis revealed altered immune cell composition, with NFE2L2 negatively correlated with activated B cell infiltration. Single\u2010cell trajectory analysis demonstrated dynamic expression of these biomarkers during differentiation of key immune cell subsets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>NFE2L2 and ZFP36L1 are potential ISR\u2010associated biomarkers in sepsis\u2010induced ARDS and may contribute to disease progression through stress\u2010response regulation and immune modulation, supporting biomarker\u2010driven risk stratification and providing a foundation for future mechanistic and interventional studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/mi\/3190064","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:06:54Z","timestamp":1788772014000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Integrated Stress Response\u2013Related 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