Asthma is a complex and heterogeneous disease characterized by chronic airway inflammation [1]. According to the inflammatory cell types in the airway, asthma can be categorized into four phenotypes: eosinophilic, neutrophilic, mixed granulocytic (presence of both eosinophils and neutrophils), and pauci-granulocytic [2]. Clinically, patients with mixed granulocytic asthma (MGA) usually require large doses of inhaled corticosteroids, which are often insufficient for controlling airway inflammation, and tend to have more severe patterns of the disease compared with other inflammatory subgroups, with much poorer lung function and higher risks of acute onset, consuming a disproportional ratio of the overall asthma-associated health care costs [[3], [4], [5]]. Therefore, it is urgent to investigate the pathophysiological mechanisms of MGA.

Airway epithelial cells represent the first physical and immunologic defense barrier against environmental threats [6]. Compromised epithelial barrier was seen in asthma, featured by shedding of ciliated cells, decreased expression of junctional molecules and increased permeability [7,8]. A growing body of studies indicate that persistent injury and abnormal repair of bronchial epithelium is a key step in the initiation and perpetuation of airway inflammation and remodeling in asthma [9,10]. Intact epithelial barrier is formed through well-coordinated assembly of tight junctions (TJs), which are composed of occludins, claudins and zonula occludens (ZO-1, 2, 3), adherens junctions (AJs) which consist of E-cadherin and catenins, and desmosomes [8]. Among those, E-cadherin is considered as a gatekeeper of the structural and immunological function of the airway epithelium [11]. Down-regulated expression of E-cadherin was seen in both clinic patients with asthma and experimental models [12,13]. By using a transgenic mouse model, researchers discovered that conditional ablation of E-cadherin in lung epithelial cells would not only affect epithelial barrier integrity but also induce asthma-like features in the airway, including spontaneous goblet cell metaplasia, mucus overproduction, elevated levels of the type-2 chemokine CCL17, as well as infiltration of eosinophils and dendritic cells [14], identifying a central role for E-cadherin in asthma. Yet the upstream mechanisms are still obscure.

Ferroptosis is a recently recognized form of regulated cell death characterized by iron-dependent accumulation of lipid hydroperoxides [15,16]. It has been implicated in multiple physiological and pathological processes, such as tumorigenesis and metastasis, tissue injury, and T-cell immunity [17]. In recent years, researchers also discovered that ferroptosis is involved in the pathogenesis of asthma. Clinical evidence revealed reduced BALF levels of cell-free iron in asthma patients, along with increased intracellular iron loading [18], which is a cardinal feature of ferroptosis [17]. Besides, other characteristic processes were found in the airway epithelium of asthmatics, including lipid peroxidation and imbalanced GSH/GSSH [19]. Inhibition of ferroptosis with a specific antagonist Liproxstatin-1 (Lip-1) significantly attenuated OVA/LPS-induced neutrophilic asthma in mice [20]. However, the role of ferroptosis in MGA is still unclear. Here, we intended to investigate the effects of ferroptosis inhibition on MGA as well as E-cadherin.