The Mechanism of VDAC1/PHB2-mediated mitophagy in regulating airway remodeling in asthma

Bronchial asthma is a heterogeneous chronic respiratory disease, with airway remodeling as its core pathological feature and a key driver of disease chronicity and refractoriness. Mitochondrial dysfunction and mitophagic dysregulation are closely involved in asthma pathogenesis, but the underlying molecular mechanisms remain unclear. This study aimed to investigate the regulatory role of the VDAC1/PHB2-mediated mitophagy axis in asthmatic airway remodeling. A house dust mite- induced mouse asthma model and an in vitro asthmatic cell model were established. Multiple experimental techniques were employed, including lung function testing, pathological staining, Western blot, co-immunoprecipitation (Co-IP), flow cytometry, and enzyme-linked immunosorbent assay. VDAC1 expression and mitophagic activity were abnormally upregulated in asthmatic model mice. VDAC1 knockdown alleviated inflammatory responses, whereas mitophagy activation by rapamycin exacerbated these pathological changes. Co-IP and immunofluorescence assays confirmed an interaction and spatial colocalization between VDAC1 and PHB2. In vitro experiments showed that VDAC1 knockdown restored cell viability, mitigated oxidative stress and mitochondrial dysfunction, and downregulated the expression of fibrosis-related proteins and inflammatory factors by inhibiting PHB2-mediated mitophagy. Conversely, PHB2 overexpression abrogated the protective effects of VDAC1 knockdown. This study reveals that VDAC1 interacts with its downstream target protein PHB2 to regulate mitophagy, thereby participating in the modulation of asthmatic airway remodeling, inflammatory responses, and cellular functions. The VDAC1-PHB2-mitophagy axis provides a novel theoretical basis and potential therapeutic target for asthma treatment.