{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:04:41Z","timestamp":1784178281343,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"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>Purpose<\/jats:title>\n                    <jats:p>Acute pulmonary contusion (APC), a life-threatening trauma-associated condition, currently lacks targeted pharmacological therapies. Fraxinellone (FRA) inhibits Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) synthesis, but its binding mechanism and anti-APC action remain unclear. This study was designed to assess the therapeutic potential of FRA, a natural substance with known anti-inflammatory properties, as a means of attenuating APC progression through the inhibition of HIF-1\u03b1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An\n                      <jats:italic>in vivo<\/jats:italic>\n                      APC model was generated via weight-drop lung injury in C57BL\/6 mice, and an\n                      <jats:italic>in vitro<\/jats:italic>\n                      model was established using thrombin (THR)-injured MLE-12 cells. The efficacy of FRA (10 \u03bcM\n                      <jats:italic>in vitro<\/jats:italic>\n                      ; 5 mg\/kg\n                      <jats:italic>in vivo<\/jats:italic>\n                      ) was evaluated through cell viability assays, measurement of inflammatory cytokines via enzyme-linked immunosorbent assay (ELISA), histopathological examination, and molecular analyses including Western blot (WB) and real-time quantitative polymerase chain reaction (RT-qPCR). Mechanistic validation was performed through HIF-1\u03b1 siRNA knockdown and mutation, ML228-mediated activation, and molecular docking simulations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FRA notably diminished APC severity by reducing pulmonary edema (wet\/dry ratio), lowering pro-inflammatory cytokine levels ((interleukin-1\u03b2 [IL-1\u03b2], interleukin-6 [IL-6], interleukin-18 [IL-18]), and decreasing pyroptosis markers (NOD-like receptor family pyrin domain containing 3 [NLRP3], gasdermin D [GSDMD]) in both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      models. Molecular docking revealed FRA binding to HIF-1\u03b1 at Arg258, and HIF-1\u03b1 activation abrogated the protective effects of FRA. HIF-1\u03b1 knockdown and mutation reproduced the anti-pyroptotic effects of FRA, confirming pathway specificity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>FRA mitigates APC progression by targeting HIF-1\u03b1 to suppress NLRP3\/GSDMD-mediated pyroptosis and inflammation, providing a novel therapeutic approach for trauma-induced lung injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1826165","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:21:28Z","timestamp":1784175688000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Fraxinellone mitigates acute lung injury by targeting HIF-1\u03b1 to suppress pyroptosis and 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