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已发表论文
慢性暴露于香烟烟雾可通过 COPD 中的 EGR1/USP44/TRAF6 轴诱导肺上皮细胞发生细胞焦亡
Authors Cao C, Zhong Z, Wu B, Zou B, Jia H, Xu J, Xiao G, Xia S
Received 13 June 2025
Accepted for publication 19 November 2025
Published 27 November 2025 Volume 2025:18 Pages 16619—16635
DOI https://doi.org/10.2147/JIR.S546865
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Editor who approved publication: Prof. Dr. Yuhan Xing
Chaofan Cao,1,2 Zhaoshuang Zhong,3 Bo Wu,4 Bo Zou,5 Hui Jia,3 Jiahuan Xu,3 Guixian Xiao,2 Shuyue Xia1,3
1Graduate School of Dalian Medical University, Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Respiratory Medicine, The Second Affiliated Hospital of Shenyang Medical College, Shenyang, Liaoning, People’s Republic of China; 3Department of Respiratory Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, People’s Republic of China; 4Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People’s Republic of China; 5Department of Respiratory Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China
Correspondence: Guixian Xiao, Email 18002453148@163.com Shuyue Xia, Email syx262@126.com
Background: Chronic obstructive pulmonary disease (COPD) is characterized by a persistent, progressive, and irreversible decline in lung function, primarily driven by persistent airway obstruction and pulmonary inflammation. Cigarette smoking is a major risk factor, as tobacco smoke harms pulmonary epithelial cells, frequently inducing chronic inflammation and ultimately resulting in structural lung lesions. Although pyroptosis is a well-recognized mechanism implicated in cigarette smoke extract (CSE)-induced lung epithelial damage, the specific regulatory roles of early growth response 1 (EGR1) and ubiquitin-specific peptidase 44 (USP44) in this process remain to be fully elucidated. Since inhibiting pyroptosis represents a promising therapeutic strategy for COPD, clarification of the roles of these factors is critically important.
Methods: We used a well-established cigarette smoke exposure protocol to establish COPD cellular and animal models. We assessed the extent of pyroptosis in the cellular model using techniques including propidium iodide (PI) staining, Annexin V/PI flow cytometry, and Western blot analysis for cleaved caspase-1 and gasdermin D (GSDMD), identified the pivotal downstream gene EGR1 through transcriptome sequencing, and validated the function of the EGR1/USP44/TNF receptor-associated factor 6 (TRAF6) axis in the model. In the animal model, we observed the therapeutic effect of USP44 knockdown on COPD progression.
Results: EGR1 was identified as a key response gene in CSE-stimulated lung epithelial cells. Moreover, our findings indicated that EGR1 plays a crucial role in facilitating CSE-induced pyroptosis. EGR1 transcriptionally enhances the expression of USP44, which subsequently facilitates the deubiquitination and stabilization of TRAF6, thus promoting pyroptosis in lung epithelial cells. The inhibition of either EGR1 or USP44 markedly reduced CSE-induced pyroptosis, underscoring their critical roles in this pathological process. Knocking down USP44 in animal models effectively alleviated COPD-like pathological changes caused by cigarette smoke exposure.
Conclusion: We identified the EGR1/USP44/TRAF6 signaling axis implicated in the pyroptosis of lung epithelial cells induced by CSE, indicating that this axis has the potential to serve as a therapeutic target for the treatment of smoking-induced COPD.
Keywords: COPD, cigarette smoke, pyroptosis, EGR1, USP44, TRAF6
1Graduate School of Dalian Medical University, Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Respiratory Medicine, The Second Affiliated Hospital of Shenyang Medical College, Shenyang, Liaoning, People’s Republic of China; 3Department of Respiratory Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, People’s Republic of China; 4Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People’s Republic of China; 5Department of Respiratory Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China
Correspondence: Guixian Xiao, Email 18002453148@163.com Shuyue Xia, Email syx262@126.com
Background: Chronic obstructive pulmonary disease (COPD) is characterized by a persistent, progressive, and irreversible decline in lung function, primarily driven by persistent airway obstruction and pulmonary inflammation. Cigarette smoking is a major risk factor, as tobacco smoke harms pulmonary epithelial cells, frequently inducing chronic inflammation and ultimately resulting in structural lung lesions. Although pyroptosis is a well-recognized mechanism implicated in cigarette smoke extract (CSE)-induced lung epithelial damage, the specific regulatory roles of early growth response 1 (EGR1) and ubiquitin-specific peptidase 44 (USP44) in this process remain to be fully elucidated. Since inhibiting pyroptosis represents a promising therapeutic strategy for COPD, clarification of the roles of these factors is critically important.
Methods: We used a well-established cigarette smoke exposure protocol to establish COPD cellular and animal models. We assessed the extent of pyroptosis in the cellular model using techniques including propidium iodide (PI) staining, Annexin V/PI flow cytometry, and Western blot analysis for cleaved caspase-1 and gasdermin D (GSDMD), identified the pivotal downstream gene EGR1 through transcriptome sequencing, and validated the function of the EGR1/USP44/TNF receptor-associated factor 6 (TRAF6) axis in the model. In the animal model, we observed the therapeutic effect of USP44 knockdown on COPD progression.
Results: EGR1 was identified as a key response gene in CSE-stimulated lung epithelial cells. Moreover, our findings indicated that EGR1 plays a crucial role in facilitating CSE-induced pyroptosis. EGR1 transcriptionally enhances the expression of USP44, which subsequently facilitates the deubiquitination and stabilization of TRAF6, thus promoting pyroptosis in lung epithelial cells. The inhibition of either EGR1 or USP44 markedly reduced CSE-induced pyroptosis, underscoring their critical roles in this pathological process. Knocking down USP44 in animal models effectively alleviated COPD-like pathological changes caused by cigarette smoke exposure.
Conclusion: We identified the EGR1/USP44/TRAF6 signaling axis implicated in the pyroptosis of lung epithelial cells induced by CSE, indicating that this axis has the potential to serve as a therapeutic target for the treatment of smoking-induced COPD.
Keywords: COPD, cigarette smoke, pyroptosis, EGR1, USP44, TRAF6