Abstract: Objective To investigate the role of voltage-dependent anion-selective channel protein 1 (VDAC1) in house dust mite (HDM)-induced asthmatic airway inflammation and its mechanism for regulating ferroptosis in airway epithelial cells. Methods Human airway epithelial (HBE) cells were exposed to a concentration gradient (200, 400 and 800 U) of HDM alone or in combination with treatment with 10 μmol/L VBIT-4 (a VDAC1 inhibitor) for 24 h, and the expressions of VDAC1 and ferroptosis-associated proteins in the cells were examined. Adult male BALB/c mice were treated with intranasal instillation of VBIT-4, HDM, or both, and the level of airway inflammation and the expressions of ferroptosis-associated proteins were detected with immunohistochemistry. Results In HBE cells, HDM exposure caused a significant increase of mitochondrial ROS (mtROS) production and obviously decreased the mitochondrial membrane potential. The exposed cells showed obviously increased protein expressions of VDAC1 (P=0.005) and FTH1 (P=0.030) but decreased protein expression of GPX4 (P=0.015) and FTH1 (P=0.037), while the treatment with VBIT-4 repressed the expression of GPX4 (P=0.001) and inhibited the expression of VDAC1. In BALB/c mice, treatment with VBIT-4 significantly improved HDM-induced airway inflammation by reducing the number of inflammatory cells (P=0.029) in the airway and the number of eosinophils in the alveolar lavage fluid. Immunohistochemical staining showed that GPX4 expression in the airway epithelial cells was significantly increased after treatment with VBIT-4. Conclusions VDAC1 participates in HDM-induced chronic airway inflammation in bronchial asthma by causing ferroptosis of the airway epithelial cells.

Key words: asthma; ferroptosis ; mitochondria; voltage-dependent anion-selective channel protein 1