Songorine protects cartilage in osteoarthritis by targeting PFKFB3 to disrupt the glycolysis-inflammation positive feedback loop

Area of Science:

• Investigates the intersection of metabolic reprogramming, epigenetic modifications, and inflammatory signaling in osteoarthritis pathogenesis.
• Focuses on the role of glycolysis and histone lactylation in chondrocyte inflammation.
• Explores the therapeutic potential of Songorine as a metabolic modulator for osteoarthritis.

Background:

• Osteoarthritis (OA) pathogenesis is increasingly linked to metabolic reprogramming within chondrocytes.
• While Songorine's effects on macrophage metabolism are known, its impact on chondrocyte metabolism and inflammation is unclear.
• Understanding Songorine's chondrocyte-specific mechanisms is crucial for developing targeted OA therapies.

Purpose of the Study:

• To investigate how Songorine regulates glycolysis-driven inflammation in OA chondrocytes.
• To elucidate a novel mechanism involving metabolic reprogramming, histone lactylation, and inflammatory signaling in OA.
• To evaluate Songorine's therapeutic potential by assessing its effects on chondrocyte metabolism and inflammation.

Main Methods:

• Utilized in vivo OA rat models and in vitro IL-1β-induced chondrocyte inflammation models.
• Performed histological, biochemical analyses, RNA sequencing, ¹³C-glucose metabolic flux, and Seahorse extracellular flux assays.
• Assessed histone lactylation via immunoblotting and CUT&Tag; evaluated Songorine-PFKFB3 interaction using molecular docking and SPR.

Main Results:

• OA cartilage showed elevated glycolysis and inflammation; Songorine treatment restored metabolic homeostasis and reduced inflammation.
• Songorine suppressed glycolytic flux, lactate production, and histone H4K12 lactylation in stimulated chondrocytes.
• Direct binding and inhibition of PFKFB3 by Songorine disrupted a positive feedback loop sustaining glycolysis and inflammation.

Conclusions:

• Songorine protects cartilage by directly targeting PFKFB3, inhibiting glycolysis-driven lactate production and histone lactylation.
• Identified a novel glycolysis-lactylation-inflammation axis critical in OA.
• Songorine demonstrates promise as a metabolic modulator for osteoarthritis therapy.