{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:03:27Z","timestamp":1790831007840,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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-induced acute lung injury (ALI) remains a devastating complication of sepsis, marked by uncontrolled pulmonary inflammation, alveolar-capillary barrier disruption, and high mortality. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is implicated in sepsis-related organ dysfunction. Moreover, a ferroptosis-related gene, Lipocalin 2 (LCN2), has been reported as a potential biomarker for sepsis-induced organ damage. However, the role and mechanism of LCN2 in sepsis-triggered ALI are still unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Transcriptomic data from GSE32707 were integrated for differential expression and WGCNA analysis. One overlapping gene was identified using key modules from WGCNA and ferroptosis-related genes from GeneCards database. LCN2 mRNA level was determined using real-time quantitative polymerase chain reaction (RT-qPCR). LCN2, Forkhead box protein A1 (FOXA1), tripartite motif-containing protein 9 (TRIM9), GPX4, SLC7A11, Occludin, and ZO-1 protein levels were detected using western blot. An\n                      <jats:italic>in vitro<\/jats:italic>\n                      model of endotoxemia was established in human pulmonary microvascular endothelial cells (HPMECs) by exposure to 10 \u00b5g\/mL LPS for 24\u00a0h, recapitulating the inflammatory and endothelial injury responses relevant to sepsis-induced ALI. Cell viability and apoptosis were detected using CCK-8 and flow cytometry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LCN2 was identified by intersecting WGCNA-derived MEsalmom and MEmidnightblue modules and ferroptosis-related genes from GeneCards database. LCN2 expression was upregulated in sepsis patients and LPS-treated HPMECs. LPS-induced HPMEC proliferation inhibition, and apoptosis, inflammatory response and ferroptosis promotion were partly abolished by LCN2 silencing. Mechanistically, FOXA1 activated LCN2 transcription by binding to its promoter region. TRIM9 promoted K48-linked polyubiquitination and subsequent degradation of LCN2. In CLP rats, LCN2 knockdown reduced lung injury and decreases pro-inflammatory cytokines, with accompanying changes in ferroptosis-related markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study demonstrates that FOXA1 transcriptionally activates LCN2, while TRIM9 promotes K48-linked ubiquitination and degradation of LCN2, together forming a dual-level regulatory mechanism that modulates ferroptosis and inflammation in LPS-treated HPMECs. Moreover, LCN2 knockdown alleviated lung injury with accompanying changes in ferroptosis-related markers in the CLP rat model, supporting the relevance of this axis\n                      <jats:italic>in vivo<\/jats:italic>\n                      . These findings identify LCN2 as a mechanistically relevant node in sepsis-induced ALI and provide a preclinical experimental basis for further validation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1822078","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:43:49Z","timestamp":1790829829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXA1-driven transcription and TRIM9-mediated ubiquitination of LCN2 modulate ferroptosis in experimental sepsis-induced acute lung injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Jin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Emergency, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, 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