LCN2-positive alveolar type II cells promote silica-induced pulmonary fibrosis via STAT3-TGF-β1-Smad3-mediated signaling

Zihao Xie; Xia Li; Mengchen Zhang; Hangbing Cao; Fei Wang; Ruiqing Yan; HuiYu Ye; Min Mu; Jianxin Wang; Fei Wang; Xinrong Tao

doi:10.1016/j.taap.2025.117579

LCN2-positive alveolar type II cells promote silica-induced pulmonary fibrosis via STAT3-TGF-β1-Smad3-mediated signaling

Toxicol Appl Pharmacol. 2025 Sep 27:505:117579. doi: 10.1016/j.taap.2025.117579. Online ahead of print.

Authors

Zihao Xie¹, Xia Li¹, Mengchen Zhang¹, Hangbing Cao², Fei Wang¹, Ruiqing Yan², HuiYu Ye², Min Mu², Jianxin Wang³, Fei Wang¹, Xinrong Tao⁴

Affiliations

¹ School of Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, China; Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China.
² Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; School of Public Health, Anhui University of Science and Technology, Hefei, Anhui 231131, China.
³ School of Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, China.
⁴ Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; School of Public Health, Anhui University of Science and Technology, Hefei, Anhui 231131, China. Electronic address: xrtao1116@hotmail.com.

PMID: 41022160
DOI: 10.1016/j.taap.2025.117579

Abstract

Lipocalin-2 (LCN2), an innate immune protein, has been identified as a potential biomarker in a range of inflammatory and fibrotic lung diseases. Nevertheless, its specific role and the underlying mechanisms in silica-induced pulmonary fibrosis remain unclear. This study found a significant increase in LCN2 expression in the lung tissues of silica-exposed mice during the stage of inflammation and fibrosis. The increased LCN2 was primarily derived from alveolar type II epithelial cells (AT2 cells). We further generated LCN2-overexpressing mouse AT2 cells (LCN2-OE AT2 cells) in vitro. These LCN2-OE AT2 cells exhibited significant upregulation of TGF-β1 and activation of Smad3, promoting the epithelial-mesenchymal transition (EMT) process. Additionally, exposure to silica in vitro led to an increase in the TGF-β1-Smad3 pathway and EMT process in AT2 cells. However, this response was effectively decreased when combined with an LCN2 inhibitor. Our findings highlight the significance of LCN2 originating from AT2 cells in both EMT and silica-induced pulmonary fibrosis, indicating a potential new treatment strategy for pulmonary fibrosis targeting LCN2.

Keywords: AT2 cells; Epithelial-mesenchymal transition; LCN2; Pulmonary fibrosis; Silica.