This study investigates the role of ferroptosis in PM2.5-induced lung injury and the potential benefits of quercetin (Que) in alleviating these effects. PM2.5, a harmful air pollutant, can lead to acute exacerbation and aggravation of respiratory diseases. Ferroptosis, an iron-dependent form of cell death, is involved in the pathological process of pulmonary disease. Quercetin, a phenolic compound, has been shown to inhibit ferroptosis in various diseases. The study used C57BL/6J mice, which were treated with saline or PM2.5 via intratracheal instillation. Quercetin was supplemented at two doses (50 mg/kg-bw and 100 mg/kg-bw). The results showed that PM2.5 exposure increased lung inflammation, lung fibrosis, lipid peroxidation, iron content, and ferroptosis markers. These effects were significantly reversed by quercetin supplementation. Quercetin also upregulated nuclear Nrf2 expression and downregulated Keap1 expression in lung tissues of PM2.5-exposed mice. In vitro, quercetin and dimethyl fumarate (DMF) decreased lipid peroxidation products, iron contents, and ferroptosis levels, and increased the nuclear translocation of Nrf2 and the degradation of Keap1 in PM2.5-exposed BEAS-2B cells. Additionally, quercetin reduced inflammatory cytokines and TGF-β1 in PM2.5-exposed cells. The study concluded that Nrf2 is involved in ferroptosis in PM2.5-induced lung injury, and quercetin can alleviate these adverse effects by activating the Nrf2-Keap1 signaling pathway.This study investigates the role of ferroptosis in PM2.5-induced lung injury and the potential benefits of quercetin (Que) in alleviating these effects. PM2.5, a harmful air pollutant, can lead to acute exacerbation and aggravation of respiratory diseases. Ferroptosis, an iron-dependent form of cell death, is involved in the pathological process of pulmonary disease. Quercetin, a phenolic compound, has been shown to inhibit ferroptosis in various diseases. The study used C57BL/6J mice, which were treated with saline or PM2.5 via intratracheal instillation. Quercetin was supplemented at two doses (50 mg/kg-bw and 100 mg/kg-bw). The results showed that PM2.5 exposure increased lung inflammation, lung fibrosis, lipid peroxidation, iron content, and ferroptosis markers. These effects were significantly reversed by quercetin supplementation. Quercetin also upregulated nuclear Nrf2 expression and downregulated Keap1 expression in lung tissues of PM2.5-exposed mice. In vitro, quercetin and dimethyl fumarate (DMF) decreased lipid peroxidation products, iron contents, and ferroptosis levels, and increased the nuclear translocation of Nrf2 and the degradation of Keap1 in PM2.5-exposed BEAS-2B cells. Additionally, quercetin reduced inflammatory cytokines and TGF-β1 in PM2.5-exposed cells. The study concluded that Nrf2 is involved in ferroptosis in PM2.5-induced lung injury, and quercetin can alleviate these adverse effects by activating the Nrf2-Keap1 signaling pathway.