Highlights

• Celastrol suppresses the SERCA pump in synovial fibroblasts, leading to autophagy-dependent cytotoxicity and the inhibition of rheumatoid arthritis progression.
• The Ca²⁺/calmodulin-dependent kinase kinase-β–AMP-activated protein kinase–mTOR pathway is the key mediator of celastrol’s anti-arthritic effects.
• The modulation of Ca²⁺ signaling pathways by celastrol offers a promising approach for the treatment of rheumatoid arthritis through the regulation of autophagy, inflammation, and immune response.

Summary

Celastrol, derived from the Chinese medicinal plant Tripterygium wilfordii Hook F, is known for its anti-arthritic properties. This research explores the therapeutic potential of celastrol in treating rheumatoid arthritis (RA) through its effects on calcium (Ca²⁺) signaling.

The study focuses on the ability of celastrol to disrupt calcium homeostasis in synovial fibroblasts from RA patients and in an experimental arthritis rat models. Key findings indicate that celastrol inhibits the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA) pump. The inhibition leads to autophagy-dependent cytotoxicity in RA synovial fibroblasts and suppression of arthritis symptoms in rats. This inhibitory effect is mediated through the activation of Ca²⁺/calmodulin-dependent kinase kinase-β–AMP-activated protein kinase–mTOR pathway.

The research also shows that the anti-arthritic effects of celastrol are dependent on Ca²⁺ signaling. By demonstrating how celastrol modulates inflammatory and autoimmunity-associated genes through disturbing of Ca²⁺ signaling, the study suggests a novel approach for RA treatment focused on manipulating this pathway.

V. K. W. Wong et al., “Ca²⁺ signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats,” British J Pharmacology, vol. 176, no. 16, pp. 2922–2944, Aug. 2019, doi: .