Transcription factor STAT1 upregulates IL-36γ to mediate the sensitivity of human nasal epithelial cells to ferroptosis and promote inflammatory progression in chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is an epidemic disease characterized by persistent inflammation and tissue remodeling of sinus mucosa, and its pathophysiology is still unclear. This study revealed the key role of the signal transducer and activator of transcription 1 (STAT1) /Interleukin-36γ (IL-36γ) signal axis in the pathogenesis of CRS for the first time. In vitro experiments showed that STAT1 overexpression can induce damage to human nasal epithelial cells (HNECs); whereas STAT1 knockdown significantly inhibits Erastin-induced Ferroptosis, as evidenced by the restoration of Ferritin Heavy Chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) expression, reduced accumulation of Acyl-CoA Synthetase Long Chain Family Member 4 and Transferrin Receptor protein 1 (TFRC) expression, and decreased Malondialdehyde (MDA) content and lipid Reactive Oxygen Species (ROS). The mechanism study showed that STAT1, as a transcription factor, regulated the IL-36γexpression by directly binding to its promoter region, thereby enhancing the sensitivity of HNECs to Ferroptosis through the upregulation of IL-36γ. Further experiments found that IL-36γ promoted the release of Ferroptosis and inflammatory cytokines, a process potentially involving the p38 MAPK pathway. In the CRS mouse model, the STAT1 Inhibitor Fludarabine can effectively alleviate pathological injury, reduce the infiltration of macrophages, CD4⁺ T cells, CD8⁺ T cells, and neutrophils, and mitigate the inflammatory reaction and Ferroptosis of the nasal mucosa. This study provides a new perspective for understanding the pathogenesis of CRS, and the discovery of the STAT1/IL-36γ signaling axis also provides a new direction for developing potential therapeutic strategies for CRS.