Combined PM2.5 and microplastics exposure exacerbates allergic asthma via OPA1/SLC7A11-mediated airway epithelial ferroptosis

This study aimed to investigate whether PM2.5 and microplastics (MPs) aggravate ovalbumin (OVA)-induced allergic airway injury and to elucidate the role of mitochondrial dysfunction-associated ferroptosis in this process. An OVA-induced murine asthma model and OVA-stimulated MRE cells were established and exposed to PM2.5 and/or MPs. Histopathological, biochemical, molecular, and functional analyses were performed to evaluate pulmonary injury, oxidative stress, ferroptosis, mitochondrial dysfunction, and inflammatory responses. In addition, OPA1 knockdown and ferrostatin-1 (Fer-1) intervention were used to verify the mechanistic involvement of ferroptosis. Exposure to PM2.5 or MPs further aggravated OVA-induced pulmonary damage, as evidenced by enhanced inflammatory infiltration, increased inflammation score, total cell counts and goblet cell percentage, and impaired lung function. In parallel, co-exposure to PM2.5 and MPs markedly intensified oxidative stress in lung tissue and MRE cells, as shown by increased ROS and MDA levels and decreased T-AOC, CAT, and SOD. Moreover, PM2.5 and MPs enhanced ferroptosis by increasing Fe 2 + accumulation, lipid peroxidation, and NCOA4, FTH1, and ACSL4 expression, while suppressing SLC7A11, GPX4, GCLC, and GSS. These effects were accompanied by profound mitochondrial dysfunction, including altered expression of mitochondria-related genes, loss of mitochondrial membrane potential, ATP depletion, reduced mitochondrial respiratory complex activities, impaired oxygen consumption rate, and decreased NADPH and GSH-related antioxidant capacity. Importantly, OPA1 silencing or Fer-1 treatment markedly attenuated PM2.5 +MPs-enhanced ferroptotic and inflammatory injury in OVA-treated MRE cells. Collectively, these findings suggest that PM2.5 and MPs co-exposure may exacerbate allergic airway injury by promoting mitochondrial dysfunction-associated ferroptosis via the OPA1/SLC7A11 pathway.