1,3,6‐Tri‐O‐Galloyl‐β‐D‐Glucose Alleviates Sepsis‐Induced Lung Damage by Inhibiting Inflammatory Response and Oxidative Stress Through Targeting Neutrophil <scp>IFIT1</scp>

Respiratory failure is a common complication of sepsis, affecting approximately 20% of patients in intensive care units worldwide, with a high mortality rate of 30%-40%. Excessive immune responses exacerbate lung damage in sepsis,; however, the key mechanisms determining survival versus susceptibility remain elusive. Elucidation of the key pathways underlying lung injury may provide novel therapeutic strategies for septic respiratory failure. This study aimed to elucidate key mechanisms regulating excessive immune responses and determining sepsis outcomes, and to provide novel intervention strategies for sepsis treatment. To achieve the above objectives, we analyzed septic immune cell heterogeneity and survival-associated hallmark genes using published single-cell RNA sequencing data from septic mice. We identified a subset of Ifit1^high neutrophils with tissue-protective potential and validated this finding using flow cytometry. Building on this, to further delineate the specific mechanism by which Ifit1 governs neutrophil immune function and thereby mediates tissue protection, our RNA sequencing-based analysis revealed that IFIT1 modulates both NFκB-driven inflammation and the NADPH oxidase pathway, ultimately conferring an anti-inflammatory effect. Furthermore, we conducted virtual screening and molecular docking to shortlist compounds with potential IFIT1-activating properties from a library of 4500 compounds. The natural compound 1,3,6-Tri-O-galloyl-β-D-glucose (TGG) demonstrated potent IFIT1 agonism, reducing LPS-induced acute inflammation both in vitro and in vivo. In summary, our research confirms that IFIT1 in neutrophils represents a novel therapeutic target for mitigating septic inflammatory storms and pulmonary dysfunction. The natural product TGG, as a potent activator of IFIT1, is a promising candidate for treating septic lung injury.