Revisiting osteoarthritis pathogenesis through the lens of cGAS-STING: Mitochondrial damage, pyroptosis, and inflammatory cascades

Osteoarthritis (OA) is associated with a multifactorial, low-grade inflammatory process involving the cGAS-STING pathway and mitochondrial dysfunction.

• The cGAS-STING pathway is activated by mitochondrial DNA leakage, which contributes to increased production of inflammatory cytokines.
• Mitochondrial dysfunction and cytoplasmic escape of mitochondrial DNA can be induced by mechanical overload, oxidative stress, and autophagy disorders.
• The presence of leaked mitochondrial DNA and reactive oxygen species can initiate and activate inflammasomes, leading to pyroptosis of cells.
• A proposed 'multilevel coupling' hypothesis suggests that the interaction between mitochondrial DNA leakage, cGAS-STING activation, and pyroptosis may sustain inflammation and accelerate OA progression.
• Targeting mitochondrial protection, cGAS-STING modulation, and inflammasome inhibition may provide new avenues for disease-modifying therapies in OA.

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