Affiliation:
1. School of Medicine, Anhui University of Science and Technology, Huainan 232001, China
2. Anhui Occupational Health and Safety Engineering Laboratory, Huainan 232001, China
3. Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institute, Huainan 232001, China
4. Key Laboratory of Industrial Dust Prevention and Control and Occupational Safety and Health Ministry of Education, Anhui University of Science and Technology, Huainan 232001, China
Abstract
Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient and low-toxicity celastrol derivative, CEL-07. In this study, we systematically investigated the therapeutic potential and underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing a silicosis mouse model and analyzing with HE, Masson, Sirius Red, and immunohistochemical staining, CEL-07 significantly prevented the progress of inflammation and fibrosis, and it effectively improved the lung respiratory function of silicosis mice. Additionally, CEL-07 markedly suppressed the expression of inflammatory factors (IL-6, IL-1α, TNF-α, and TNF-β) and fibrotic factors (α-SMA, collagen I, and collagen III), and promoted apoptosis of fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined with experimental validation revealed that CEL-07 inhibited the pathways associated with inflammation (PI3K-AKT and JAK2-STAT3) and the expression of apoptosis-related proteins. Overall, these results suggest that CEL-07 may serve as a potential candidate for the treatment of silicosis.
Funder
university-level key projects of Anhui University of Science and Technology
Open Research Fund of Anhui Province Engineering Laboratory of Occupational Health and Safety
Scientific Research Foundation for High-level Talents of Anhui University of Science and Technology
Practice Innovation Training Program for College Students in Anhui Province
National Natural Science Foundation of China
Collaborative Innovation Project of Colleges and Universities of Anhui Province
Anhui Province Engineering Laboratory of Occupational Health and Safety
Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes
Undergraduate Innovation and Entrepreneurship Training Program
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