{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:53:51Z","timestamp":1781844831244,"version":"3.54.5"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"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>Background<\/jats:title>\n                    <jats:p>Traumatic lung injury (TLI) frequently progresses to acute respiratory distress syndrome (ARDS), a condition with high mortality and limited targeted therapies. This study aimed to identify specific immune cell drivers and potential therapeutic targets for precision intervention in TLI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data from peripheral blood mononuclear cells of trauma patients, transcriptomic data from alveolar macrophages in ARDS patients, and lung tissue transcriptomic data from a TLI mouse model. An integrated bioinformatics approach was employed, including the use of the Augur and Milo algorithms for prioritizing cellular perturbations, Monocle 3 for trajectory inference, and two-sample Mendelian randomization (TSMR) for causal inference. Potential drugs were screened using Connectivity Map, target-specificity predictions were made using the scRANK algorithm, and validation was performed using an\n                      <jats:italic>in vitro<\/jats:italic>\n                      macrophage polarization model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The scRNA-seq analyses revealed that classical monocytes showed the greatest disturbance and response following trauma. Among these, the ISG15+STAT1+ monocyte subpopulation expanded post-trauma and drove an inflammatory storm through robust M1-like polarization. PIM1 was identified as a core pathogenic gene co-upregulated in both peripheral blood and lung tissue. Further TSMR analysis confirmed elevated PIM1 expression as a causal risk factor for ARDS. Concurrently, the JAK2\/STAT3\/PIM1 pathway is activated synchronously during the acute trauma phase. Drug repurposing research suggests that the JAK2 inhibitor Fedratinib can reverse the transcriptomic characteristics of TLI.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments have demonstrated that Fedratinib effectively inhibits M1 polarization and the expression of inflammatory genes by interfering with the JAK2\/STAT3\/PIM1 signaling axis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identifies the JAK2\/STAT3\/PIM1 signaling axis within the ISG15+STAT1+ monocyte subpopulation as a key driver of TLI and a potential therapeutic target, and suggests that fedratinib is a potential candidate for the targeted treatment of TLI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1843701","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:29:43Z","timestamp":1781843383000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the ISG15+STAT1+ monocyte-driven inflammatory storm with Fedratinib in traumatic lung injury via the JAK2\/STAT3\/PIM1 axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Kun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, 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