Celastrol alleviates synovial inflammation and joint destruction in rheumatoid arthritis in association with Nrf2/HO-1/GPX4 pathway activation.

Abstract

Rheumatoid arthritis (RA) is characterized by persistent synovial inflammation, oxidative imbalance, and progressive joint destruction. Celastrol (CEL), a bioactive triterpenoid derived from Tripterygium wilfordii, exhibits anti-inflammatory and antioxidant activities, but its mechanism of action in RA remains incompletely defined. This study investigated whether the Nrf2/HO-1/GPX4 pathway is involved in the protective effects of CEL in RA. Collagen-induced arthritis (CIA) rats were treated with CEL or methotrexate for 4 weeks. Arthritis severity, serum inflammatory cytokines, histopathological injury, oxidative stress, and pathway-related proteins were evaluated. In vitro, TNF-α-stimulated fibroblast-like synoviocytes (FLS) were used to assess proliferation, migration, invasion, apoptosis, inflammatory responses, and ROS/Fe²⁺ accumulation. tBHQ and Brusatol were used as pharmacological pathway-modulating probes in functional and rescue experiments. CEL significantly reduced paw swelling, arthritis scores, and serum IL-1β, IL-6, and TNF-α levels in CIA rats, and attenuated synovial hyperplasia, cartilage damage, collagen loss, and osteoclast activation. CEL also increased Nrf2, HO-1, and GPX4 expression while reducing ROS and Fe2+ accumulation in ankle-joint-derived single-cell suspensions. In TNF-α-stimulated rat FLS, CEL suppressed proliferation, migration, and invasion, increased apoptosis under inflammatory stimulation, and alleviated inflammatory and oxidative stress responses. These protective effects were pharmacologically enhanced by tBHQ and attenuated by Brusatol co-treatment. These findings suggest that CEL alleviates synovial inflammation and joint injury in experimental RA in association with Nrf2/HO-1/GPX4 pathway activation and suppression of TNF-α-stimulated rat FLS activation, supporting further investigation of CEL as a candidate antioxidant-oriented therapeutic agent for RA.

Key Findings

• Celastrol significantly reduced arthritis severity, serum inflammatory cytokines, and joint damage in collagen-induced arthritis rats.
• Celastrol increased expression of Nrf2, HO-1, and GPX4 while reducing ROS and Fe2+ accumulation in joint tissues.
• In TNF-α-stimulated fibroblast-like synoviocytes, celastrol suppressed proliferation, migration, invasion, and inflammatory responses, effects enhanced by Nrf2 activator tBHQ and attenuated by inhibitor Brusatol.

Clinical Significance

Citation

Guo Yunke, Tang Hao, Musha Aydanaet al.. Celastrol alleviates synovial inflammation and joint destruction in rheumatoid arthritis in association with Nrf2/HO-1/GPX4 pathway activation. Molecular and cellular biochemistry. 2026-Aug-28.