Ferroptosis inhibition and mitochondrial rescue: a novel mechanism of emodin in rheumatoid arthritis

Objectives: Rheumatoid arthritis (RA) is characterized by chronic synovitis and progressive joint destruction. Ferroptosis has been implicated in RA pathogenesis through synovial iron accumulation and oxidative stress. Glutathione Peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) are key regulators of Ferroptosis, but their specific roles in RA remain incompletely defined. The objective of this research was to explore the therapeutic effects and the mechanisms behind emodin (EMO) in RA.

Methods: The therapeutic efficacy and mechanisms of EMO were evaluated in collagen-induced arthritis mice and lipopolysaccharide-stimulated RAW264.7 macrophages. Joint pathology, inflammation, oxidative stress, Ferroptosis, and mitochondrial function were analyzed using histology, micro-computed tomography, western blotting, immunohistochemistry, and microscopy. Key targets were identified and validated using molecular dynamics, molecular docking, proteomics, and network pharmacology.

Results: EMO alleviated joint inflammation and bone destruction, reduced pro-inflammatory cytokines and oxidative stress, restored iron and mitochondrial homeostasis, and inhibited Ferroptosis. Mechanistically, EMO inhibited Ferroptosis through the GPX4/ACSL4 axis, as evidenced by increased GPX4 and decreased ACSL4 expression.

Conclusions: EMO ameliorates experimental arthritis mainly by suppressing Ferroptosis via the GPX4/ACSL4 axis, highlighting Ferroptosis as a previously underappreciated therapeutic target in RA and supporting EMO as a potential adjunctive treatment for RA.

Rheumatoid arthritis; emodin; ferroptosis; mitochondria; oxidative stress.