Tang Yuanyuan, Wu Han, Yan Ping, Yue Zhangxuan, Hu Zeyu, Liao Xunqi, Wang Yali, Lin Ye, Li Liqing, Cai Xiong
Institutes of Chinese Medicine and Materia Medica and School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
Institutes 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, China.
Pharmacol Res. 2025 Jun;216:107762. doi: 10.1016/j.phrs.2025.107762. Epub 2025 May 8.
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.
类风湿关节炎（RA）是一种具有挑战性的自身免疫性疾病，其特征是成纤维样滑膜细胞（FLS）驱动的滑膜炎和关节破坏。常山酮（HF）是从常山（Dichroa febrifuga Lour.）根中分离出的 febrifugine 的生物活性衍生物，在 RA 中显示出治疗潜力，但其分子靶点仍有待阐明。在本研究中，我们证明口服 HF 治疗（1.25 和 2.5 mg/kg，隔日一次）可显著抑制佐剂诱导的关节炎（AIA）大鼠的疾病进展，表现为滑膜增生、软骨破坏和骨侵蚀程度明显减轻。通过表面等离子体共振（SPR）分析证实 HF（0.1 - 0.8 μM）通过靶向热休克蛋白家族 A 成员 8（HSPA8）对 RA-FLS 的增殖、侵袭和炎症反应产生剂量依赖性抑制，显示直接结合（KD = 3.877 μM）。值得注意的是，与对照组相比，HSPA8 在 AIA 滑膜组织和 RA-FLS 中显著过表达。HSPA8 的 siRNA 敲低显著降低了 RA-FLS 的增殖、侵袭和炎症反应，而 HSPA8 的腺病毒过表达则加剧了这些表型。机制上，HF 显著降低了 AIA 大鼠滑膜和 RA-FLS 中 HSPA8 的表达。这些发现确立了 HSPA8 作为 RA 的新型治疗靶点，并验证了 HF 作为其天然抑制剂，为靶向 HSPA8 的 RA 治疗提供了机制见解。
