Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes
Rheumatoid arthritis (RA) is a challenging autoimmune disorder characterized by fibroblast-like synoviocyte (FLS)-driven synovitis and joint destruction. Halofuginone (HF), a bioactive derivative of febrifugine isolated from the root of Dichroa febrifuga Lour., exhibits therapeutic potential in RA y...
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Elsevier
2025-06-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825001872 |
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| author | Yuanyuan Tang Han Wu Ping Yan Zhangxuan Yue Zeyu Hu Xunqi Liao Yali Wang Ye Lin Liqing Li Xiong Cai |
| author_facet | Yuanyuan Tang Han Wu Ping Yan Zhangxuan Yue Zeyu Hu Xunqi Liao Yali Wang Ye Lin Liqing Li Xiong Cai |
| author_sort | Yuanyuan Tang |
| collection | DOAJ |
| description | Rheumatoid arthritis (RA) is a challenging autoimmune disorder characterized by fibroblast-like synoviocyte (FLS)-driven synovitis and joint destruction. Halofuginone (HF), a bioactive derivative of febrifugine isolated from the root of Dichroa febrifuga Lour., exhibits therapeutic potential in RA yet its molecular targets remain to be elucidated. In this study, we demonstrated that oral HF treatment (1.25 and 2.5 mg/kg, every other day) significantly inhibited disease progression of adjuvant-induced arthritis (AIA) in rats manifested by markedly less extent of synovial proliferation, cartilage destruction, and bone erosion. HF (0.1–0.8 μM) exerted dose-dependent inhibition on RA-FLS proliferation, invasion, and inflammatory response via targeting HSPA8 as confirmed by surface plasmon resonance (SPR) analysis showing direct binding (KD=3.877 μM). Notably, HSPA8 exhibited pronounced overexpression in AIA synovial tissue and RA-FLS versus controls. siRNA knockdown of HSPA8 significantly reduced RA-FLS proliferation, invasion, and inflammatory response, while adenoviral overexpression of HSPA8 exacerbated these phenotypes. Mechanistically, HF markedly reduced HSPA8 expression in the synovium of AIA rats and RA-FLS. These findings establish HSPA8 as a novel therapeutic target in RA and validate HF as its natural inhibitor, providing mechanistic insights for HSPA8-targeted RA therapies. |
| format | Article |
| id | doaj-art-618c85013771403b8e577cf0afe5c2fd |
| institution | OA Journals |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-618c85013771403b8e577cf0afe5c2fd2025-08-20T02:32:19ZengElsevierPharmacological Research1096-11862025-06-0121610776210.1016/j.phrs.2025.107762Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytesYuanyuan Tang0Han Wu1Ping Yan2Zhangxuan Yue3Zeyu Hu4Xunqi Liao5Yali Wang6Ye Lin7Liqing Li8Xiong Cai9Institutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, ChinaInstitutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, ChinaInstitutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; The Central Research Laboratory, Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, ChinaInstitutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, ChinaInstitutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, ChinaInstitutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, ChinaInstitutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, ChinaInstitutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Corresponding authors.The Central Research Laboratory, Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Corresponding authors.Institutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Corresponding authors.Rheumatoid arthritis (RA) is a challenging autoimmune disorder characterized by fibroblast-like synoviocyte (FLS)-driven synovitis and joint destruction. Halofuginone (HF), a bioactive derivative of febrifugine isolated from the root of Dichroa febrifuga Lour., exhibits therapeutic potential in RA yet its molecular targets remain to be elucidated. In this study, we demonstrated that oral HF treatment (1.25 and 2.5 mg/kg, every other day) significantly inhibited disease progression of adjuvant-induced arthritis (AIA) in rats manifested by markedly less extent of synovial proliferation, cartilage destruction, and bone erosion. HF (0.1–0.8 μM) exerted dose-dependent inhibition on RA-FLS proliferation, invasion, and inflammatory response via targeting HSPA8 as confirmed by surface plasmon resonance (SPR) analysis showing direct binding (KD=3.877 μM). Notably, HSPA8 exhibited pronounced overexpression in AIA synovial tissue and RA-FLS versus controls. siRNA knockdown of HSPA8 significantly reduced RA-FLS proliferation, invasion, and inflammatory response, while adenoviral overexpression of HSPA8 exacerbated these phenotypes. Mechanistically, HF markedly reduced HSPA8 expression in the synovium of AIA rats and RA-FLS. These findings establish HSPA8 as a novel therapeutic target in RA and validate HF as its natural inhibitor, providing mechanistic insights for HSPA8-targeted RA therapies.http://www.sciencedirect.com/science/article/pii/S1043661825001872Rheumatoid arthritisFibroblast-like synoviocytesHalofuginoneHSPA8Adjuvant-induced arthritis |
| spellingShingle | Yuanyuan Tang Han Wu Ping Yan Zhangxuan Yue Zeyu Hu Xunqi Liao Yali Wang Ye Lin Liqing Li Xiong Cai Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes Pharmacological Research Rheumatoid arthritis Fibroblast-like synoviocytes Halofuginone HSPA8 Adjuvant-induced arthritis |
| title | Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes |
| title_full | Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes |
| title_fullStr | Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes |
| title_full_unstemmed | Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes |
| title_short | Targeting overexpressed HSPA8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes |
| title_sort | targeting overexpressed hspa8 by halofuginone suppresses aberrant proliferation and invasion of rheumatoid arthritis fibroblast like synoviocytes |
| topic | Rheumatoid arthritis Fibroblast-like synoviocytes Halofuginone HSPA8 Adjuvant-induced arthritis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825001872 |
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