FOXP1 exacerbates allergic rhinitis progression by mediating ferroptosis in nasal mucosal epithelial cells via transcriptional regulation of SDHAF2.

OBJECTIVE: To investigate the role of the transcription factor FOXP1 and its target gene SDHAF2 in allergic rhinitis (AR), as well as their regulatory effects on ferroptosis in nasal epithelial cells. METHODS: An AR mouse model and IL-4/IL-13-induced human nasal epithelial cells (HNEpCs) were used. Gene and protein expression, cytokine secretion, ferroptosis markers, nasal pathology, and AR symptoms were assessed via transcriptome sequencing, qRT-PCR, Western blot, ELISA, dual-luciferase reporter assay, co-immunoprecipitation, detection of Fe2+, ROS, GSH, MDA and lipid peroxides (LPO), and transmission electron microscopy. The biological functions of FOXP1 and SDHAF2 were explored through gene knockdown or overexpression, combined with the intervention of ferroptosis activator Erastin or inhibitor Ferrostatin-1. RESULTS: Sdhaf2 was significantly upregulated in AR models and closely associated with mitochondrial function and ferroptosis. Knockdown of SDHAF2 inhibited IL-4/IL-13-induced ferroptosis and inflammation in HNEpCs, whereas overexpression of SDHAF2 aggravated these phenotypes. The above changes could be modulated by Erastin or Ferrostatin-1. FOXP1 was highly expressed in AR models and transcriptionally regulated SDHAF2, which was verified by dual-luciferase reporter assays. SDHAF2 interacted with ALOX15 to increase ALOX15 expression and promote ferroptosis. Additional overexpression of ALOX15 reversed the inhibitory effect of SDHAF2 knockdown on ferroptosis. In OVA-induced AR mice, Sdhaf2 knockdown relieved nasal symptoms, reduced inflammatory cytokines, improved nasal pathological lesions and suppressed ferroptosis, and these protective effects were partially abolished by Erastin. CONCLUSION: FOXP1 upregulates SDHAF2. The encoded SDHAF2 protein interacts with ALOX15 to facilitate ferroptosis in nasal epithelial cells, thereby aggravating AR progression. The FOXP1/SDHAF2/ALOX15/ferroptosis axis may serve as a novel therapeutic target for AR.