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已发表论文
大黄素通过直接作用于 TAK1 缓解单甲基新斯的明诱导的肺动脉高压
Authors Zhang Y, Zhang M, Li T, Liu Y, Li Z, Zhou L, Hu Y
Received 6 June 2025
Accepted for publication 24 September 2025
Published 30 September 2025 Volume 2025:19 Pages 8843—8864
DOI https://doi.org/10.2147/DDDT.S540915
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Tuo Deng
Yaolei Zhang,1,2 Mingmei Zhang,3 Ting Li,2 Yunchuan Liu,1 Zihan Li,4 Longfu Zhou,5 Yonghe Hu1,4
1School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, People’s Republic of China; 2Clinical Biobank Center, General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 3Department of Rheumatology and Immunology, General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 4College of Medicine, Southwest Jiaotong University, Chengdu, People’s Republic of China; 5Department of Biomedical Engineer, General Hospital of Western Theater Command, Chengdu, People’s Republic of China
Correspondence: Yonghe Hu, School of Materials Science and Engineering, Southwest Jiaotong University, No. 111, North Section 1, Second Ring Road, Chengdu, Sichuan, 610031, People’s Republic of China, Tel +86 028-86571619, Email yonghehu123@163.com
Purpose: Pulmonary arterial hypertension (PAH) is a group of diseases characterized by elevated pulmonary arterial pressure. The malignant proliferation of pulmonary artery smooth muscle cells is a major pathological hallmark of PAH. Emodin, a natural compound with known antiviral, anti-inflammatory, and anti-proliferative properties, has shown potential in alleviating PAH. Our aim is to elucidate the core pathways and molecular targets through which emodin exerts its therapeutic effects in alleviating PAH.
Methods: Firstly, potential targets of emodin in alleviating PAH were predicted using network pharmacology. Molecular docking was used to predict the binding affinity between emodin and its targets, and the interactions between emodin and these targets were verified using the Cellular Thermal Shift Assay, Co-immunoprecipitation, and Immunofluorescence. Ultrasound and pathological analyses were employed to evaluate the effects of emodin on monocrotaline-induced PAH. Finally, the results obtained from network pharmacology were validated using hematoxylin and eosin staining, ultrasound imaging, Western blotting, and polymerase chain reaction.
Results: Emodin relieves PAH by inhibiting PASMC proliferation, reducing right ventricular hypertrophy, and decreasing lung inflammation. It targets eight proteins in 15 pathways, including IL-17 signaling. Molecular docking shows emodin binds to key IL-17 pathway molecules, reducing IL-17A, IL-17RA, and Phospho-TAK1 expression. Emodin binds competitively to TAK1, preventing its interaction with MKK3, inhibiting TAK1 phosphorylation and downstream pathway activation, thus suppressing inflammation. The indispensable role of TAK1 in mediating emodin’s effects was corroborated through pharmacological blockade with Takinib, a highly potent and selective TAK1 inhibitor.
Conclusion: The experiment has demonstrated for the first time that emodin directly targets TAK1, downregulates the expression of IL-17A, IL-17RA, and Phospho-TAK1, blocks the activation of the IL-17 signaling pathway, inhibits PASMCs proliferation, and alleviates PAH. This study provides a theoretical basis for the clinical application of emodin.
Keywords: emodin, pulmonary arterial hypertension, network pharmacology, TAK1, IL-17 signaling pathway
1School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, People’s Republic of China; 2Clinical Biobank Center, General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 3Department of Rheumatology and Immunology, General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 4College of Medicine, Southwest Jiaotong University, Chengdu, People’s Republic of China; 5Department of Biomedical Engineer, General Hospital of Western Theater Command, Chengdu, People’s Republic of China
Correspondence: Yonghe Hu, School of Materials Science and Engineering, Southwest Jiaotong University, No. 111, North Section 1, Second Ring Road, Chengdu, Sichuan, 610031, People’s Republic of China, Tel +86 028-86571619, Email yonghehu123@163.com
Purpose: Pulmonary arterial hypertension (PAH) is a group of diseases characterized by elevated pulmonary arterial pressure. The malignant proliferation of pulmonary artery smooth muscle cells is a major pathological hallmark of PAH. Emodin, a natural compound with known antiviral, anti-inflammatory, and anti-proliferative properties, has shown potential in alleviating PAH. Our aim is to elucidate the core pathways and molecular targets through which emodin exerts its therapeutic effects in alleviating PAH.
Methods: Firstly, potential targets of emodin in alleviating PAH were predicted using network pharmacology. Molecular docking was used to predict the binding affinity between emodin and its targets, and the interactions between emodin and these targets were verified using the Cellular Thermal Shift Assay, Co-immunoprecipitation, and Immunofluorescence. Ultrasound and pathological analyses were employed to evaluate the effects of emodin on monocrotaline-induced PAH. Finally, the results obtained from network pharmacology were validated using hematoxylin and eosin staining, ultrasound imaging, Western blotting, and polymerase chain reaction.
Results: Emodin relieves PAH by inhibiting PASMC proliferation, reducing right ventricular hypertrophy, and decreasing lung inflammation. It targets eight proteins in 15 pathways, including IL-17 signaling. Molecular docking shows emodin binds to key IL-17 pathway molecules, reducing IL-17A, IL-17RA, and Phospho-TAK1 expression. Emodin binds competitively to TAK1, preventing its interaction with MKK3, inhibiting TAK1 phosphorylation and downstream pathway activation, thus suppressing inflammation. The indispensable role of TAK1 in mediating emodin’s effects was corroborated through pharmacological blockade with Takinib, a highly potent and selective TAK1 inhibitor.
Conclusion: The experiment has demonstrated for the first time that emodin directly targets TAK1, downregulates the expression of IL-17A, IL-17RA, and Phospho-TAK1, blocks the activation of the IL-17 signaling pathway, inhibits PASMCs proliferation, and alleviates PAH. This study provides a theoretical basis for the clinical application of emodin.
Keywords: emodin, pulmonary arterial hypertension, network pharmacology, TAK1, IL-17 signaling pathway