2. Academic Validation
  3. Tussilagone attenuated cigarette smoke-induced chronic obstructive pulmonary disease through regulating Nrf2 and NF-κB/NLRP3 inflammasome via directly targeting cysteine 434 of KEAP1

Tussilagone attenuated cigarette smoke-induced chronic obstructive pulmonary disease through regulating Nrf2 and NF-κB/NLRP3 inflammasome via directly targeting cysteine 434 of KEAP1

  • J Adv Res. 2025 Jul 14:S2090-1232(25)00544-2. doi: 10.1016/j.jare.2025.07.019.
Lin-Tao Xu 1,  Qing-Tong Han 2,  Zhen-Peng Xu 1,  Xiao-Ning Wang 1,  Hua Zhang 3,  Tao Shen 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University, Jinan 250012, China; Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Shandong Provincial Key Laboratory of Bioactive Components and Translational Research of Traditional Chinese Medicine, Shandong University, Jinan 250012, China.
  • 2 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University, Jinan 250012, China; Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Shandong Provincial Key Laboratory of Bioactive Components and Translational Research of Traditional Chinese Medicine, Shandong University, Jinan 250012, China. Electronic address: hanqingtong@sdu.edu.cn.
  • 3 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: bio_zhangh@ujn.edu.cn.
  • 4 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University, Jinan 250012, China; Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Shandong Provincial Key Laboratory of Bioactive Components and Translational Research of Traditional Chinese Medicine, Shandong University, Jinan 250012, China. Electronic address: shentao@sdu.edu.cn.
PMID: 40669599 DOI: 10.1016/j.jare.2025.07.019
Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) represents a significant global health challenge, characterized by substantial morbidity and mortality rates. In traditional Chinese medicine (TCM), Farfarae Flos (FF) has been widely utilized as a therapeutic agent for COPD. However, its specific bioactive compounds and the underlying mechanisms are unclear.

Objectives: This study aims to identify bioactive constituent of FF against COPD and illustrate its therapeutic target and mechanism.

Methods and results: In this research, a high-throughput screening on constituents of FF was conducted, leading to the identification of a potent anti-COPD lead, tussilagone (TUS). Utilizing biotin-labeling approach, Kelch-like ECH-associated protein 1 (KEAP1), the ubiquitin E3 Ligase of nuclear factor erythroid 2-related factor 2 (Nrf2), was identified to be the direct target of TUS. Mechanistically, TUS activated Keap1-Nrf2 axis by covalent modification of cysteine 434 (Cys434), a novel high-reactivity cysteine of KEAP1. TUS-mediated Nrf2 activation further suppressed the activation of nuclear factor kappa-B (NF-κB) and NOD-like Receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, consequently attenuating lung inflammation in COPD.

Conclusion: TUS was identified as the bioactive constituent of FF against COPD, which directly targeted Cys434 of KEAP1. KEAP1 was proven to be a pharmacological target for the treatment of COPD, and Cys434 was identified to be the first highly reactive cysteine in Kelch domain of KEAP1. TUS inhibits lung inflammation by regulating Nrf2 and NF-κB/NLRP3, which is the mechanism of FF against COPD.

Keywords

Chronic obstructive pulmonary disease; Inflammation; KEAP1; Tussilagone.

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