{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:25:41Z","timestamp":1777861541644,"version":"3.51.4"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"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>Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and is associated with high mortality in intensive care units. Septic cardiomyopathy (SCM) is a frequent and severe complication of sepsis; however, its underlying molecular mechanisms and immune regulatory networks remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Transcriptomic profiling of septic mouse myocardium was performed to characterize hypoxia-associated immune remodeling at both bulk and single-cell levels. Hypoxia-related genes were identified through integrative differential expression and network analyses. These candidate genes were mapped to human peripheral blood transcriptomic datasets for machine learning\u2013based biomarker selection, followed by two-sample Mendelian randomization analysis to assess their causal relevance to sepsis.\n                      <jats:italic>In vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments were conducted to validate the mechanistic involvement of key genes in septic cardiomyopathy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Septic myocardium exhibited prominent activation of hypoxia-related signaling accompanied by immune landscape remodeling, characterized by increased macrophage infiltration. NFIL3, TGM2, and SDC4 were identified as key hypoxia-associated hub genes and showed robust diagnostic performance in independent human peripheral blood cohorts. Two-sample Mendelian randomization analysis demonstrated that genetically predicted higher NFIL3 expression was significantly associated with increased sepsis risk. Single-cell analysis revealed predominant enrichment of\n                      <jats:italic>Nfil3<\/jats:italic>\n                      in macrophages. Consistently,\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments confirmed time-dependent upregulation of NFIL3 and HIF-1\u03b1 in myocardial macrophages during sepsis, with evident spatial colocalization. Functional experiments further demonstrated that NFIL3 negatively regulates macrophage inflammatory responses, at least in part through inhibition of NF-\u03baB signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study systematically delineates the molecular basis of septic cardiomyopathy, highlighting hypoxia-driven immune dysregulation as a central pathogenic mechanism. As a key hypoxia-responsive immune regulator, NFIL3 may play a critical role in the development of septic cardiac injury. These findings identify novel molecular targets for the early diagnosis and therapeutic intervention of sepsis and its associated myocardial damage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1785241","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:24:53Z","timestamp":1777523093000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics analysis identifies NFIL3 as a hypoxia-associated immune regulator in septic cardiomyopathy"],"prefix":"10.3389","volume":"17","author":[{"given":"Haibei","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine and Emergency, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxiao","family":"Feng","sequence":"additional","affiliation":[{"name":"Department 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