Melatonin alleviates rheumatoid arthritis via elimination of damaged mitochondria

Jun 15, 2026Autophagy

Melatonin may ease rheumatoid arthritis by removing damaged cell energy parts

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Melatonin significantly alleviates collagen or K/BxN serum-induced arthritis in mouse models.

Melatonin activates melatonin receptor 1A, which may promote the process of mitophagy.
Mitophagy is associated with the elimination of reactive oxygen species and leaked mitochondrial DNA from damaged mitochondria.
Reduced levels of reactive oxygen species and mitochondrial DNA could limit the activation of the NLRP3 inflammasome.
Increased NLRP3 inflammasome activation is linked to higher pro-inflammatory cytokine release.
Mice lacking the autophagy-related gene in myeloid cells show minimal therapeutic benefits from melatonin.

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Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease primarily characterized by symmetrical synovial inflammation, leading to joint swelling, pain, and progressive cartilage and bone destruction. Unfortunately, the clinical treatment of RA still faces numerous challenges. Although melatonin (MT), the circadian rhythm hormone, is known to relieve the pathological process of RA, the underlying mechanism remains poorly understood. Herein, we assess the impacts of MT on collagen or K/BxN serum-induced arthritis (two well-established models of RA) and confirm its excellent therapeutic effect. Mechanistically, MT activates MTNR1A (melatonin receptor 1A) to promote mitophagy for the elimination of reactive oxygen (ROS) and leaked mitochondrial DNA triggered by damaged mitochondria, which in turn limits NLRP3 (NLR family pyrin domain containing 3) inflammasome activation and pro-inflammatory cytokine release. Mice with deletion of the autophagy-related genein myeloid cells () barely display any benefits of MT in K/BxN serum-induced arthritis. Our results indicate that mitophagy promoted by MT is essential to deactivate NLRP3 inflammasome and alleviate the development of arthritis, which provides a candidate for the treatment of RA. Atg5atg5Lyz2/LysM-cre fl/fl

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Melatonin alleviates rheumatoid arthritis via elimination of damaged mitochondria

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