Urbanization and industrialization inevitably brought atmospheric pollution, which has become an environmental health threat globally [1]. Particulate matter (PM) is the primary component of atmospheric pollutants. The aerodynamic characteristics of PM allow its extensive deposition in the lung from bronchial to alveolar epithelium. Epidemiological and fundamental research have demonstrated that ubiquitous PM exposure is substantially linked with increased mortality and morbidity of people suffering from respiratory diseases ranging from bronchitis to lung cancer [2]. PM-induced lung injury (PMLI) is fundamentally associated with the pathogenesis and progression of various respiratory diseases. However, the molecular process responsible for PM’s biohazardous effects requires further elucidation.

Oxidative stress (OS) is caused by the imbalance between the anti-oxidation systems and intrinsic oxidation and is the manifestation of increased synthesis of reactive oxygen species (ROS). The OS is considered the primary cellular reaction to PM exposure. The direct OS biomarker is ROS, whereas the indirect biomarkers comprise malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). The literature suggests that excess ROS causes lipid peroxidation, which induces PM’s cytotoxic effects, causing pulmonary epithelial-regulated cellular death, which involves apoptosis, pyroptosis, necroptosis, ferroptosis, etc. [3]. Ferroptosis is a novel iron-dependent programmed cellular death that results from increased lipid peroxidation to a lethal level depending on OS [4]. Ferroptosis’s biochemical mechanism includes the suppression of the cystine/glutamate antiporter system (system Xc-), depletion of GSH, and inhibition of glutathione peroxidase 4 (GPX4) [5]. The cystine/glutamate transporter solute carrier family 7 member 11 (SLC7A11) is an integral component of system Xc- and induces cystine uptake, which promotes GSH synthesis, a critical antioxidant that scavenges lipid peroxides. Subsequently, GPX4 utilizes GSH to detoxify lipid peroxidation, thereby inhibiting ferroptosis. The dysregulation of the SLC7A11/GPX4 axis causes lipid peroxidation-mediated ferroptotic cell death. It has been indicated that pulmonary epithelial ferroptosis is involved in the pathogenesis of PMLI [6], [7], [8]. The ferroptotic epithelial cell death impairs the structural integrity of pulmonary epithelium and exhibits a pro-inflammatory effect. Therefore, manipulating pathological pulmonary epithelial ferroptosis might be a promising treatment strategy for PMLI.

FGF10 released from lung mesenchymal cells, belongs to the fibroblast growth factor (FGF) family and is essentially associated with lung development, FGF10 is critical for lung repair and regeneration after injury [9], [10]. FGF10 exhibits its protective effect in PMLI, partially by regulating pyroptosis. However, whether FGF10 exerts a similar modulatory effect on ferroptosis remains undetermined. Anti-ferroptotic effects of FGF family members have been observed, such as FGF2 in microvascular ischemia–reperfusion injury and FGF21 in iron overload-induced liver injury [11], [12]. Moreover, nuclear factor erythroid-2-related factor (Nrf2) signaling contributes to ferroptosis resistance by regulating gene expression through maintaining redox homeostasis and iron metabolism. Previous research has identified FGF10 as a novel OS modulator whose anti-oxidative impact relies on Nrf2 signaling [13], [14], [15], [16]. Nrf2 signaling modulates the expression of antioxidant factors, such as quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1 (HO-1). Besides, Nrf2 signaling also regulates SLC7A11/GPX4 axis, which prevents ferroptotic cell death [17]. Based on the intrinsic characteristic of ferroptosis and the anti-oxidative effect of FGF10, it is essential to elucidate the potential regulatory effect of exogenous FGF10 on pulmonary epithelial ferroptosis upon PM exposure.

Based on the literature review, it was hypothesized that FGF10 protects against PMLI by regulating pulmonary epithelial ferroptosis and that the anti-ferroptotic effect of FGF10 was at least partially mediated by Nrf2 signaling. In this investigation, C57BL/6 mice exposed to PM were given FGF10 intervention for in vivo analysis, and for in vitro analysis, human bronchial epithelial cells (HBECs) were used for assessing FGF10′s downstream molecular mechanism.