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

BACKGROUND

Metabolic reprogramming has recently been recognized as a critical driver in the development and progression of osteoarthritis (OA). While Songorine has been shown to modulate macrophage metabolism, its direct effects on chondrocyte metabolism and inflammation remain poorly understood.

PURPOSE: This study set out to explore how Songorine regulates glycolysis-driven inflammation in OA chondrocytes and to elucidate a novel mechanism linking metabolic reprogramming, histone lactylation, and inflammatory signaling.

STUDY

DESIGN

We utilized both in vivo OA rat models and in vitro IL-1β-induced chondrocyte inflammation models to assess Songorine's metabolic and anti-inflammatory effects.

METHODS

Histological and biochemical analyses were performed on OA rat joints to evaluate cartilage degeneration, metabolic alterations, and inflammatory markers. RNA sequencing, ¹³C-glucose metabolic flux assays, and Seahorse extracellular flux analysis were used to characterize glycolytic activity. Histone lactylation levels were assessed by immunoblotting and CUT&Tag. The binding between Songorine and PFKFB3 was evaluated by molecular docking and surface plasmon resonance (SPR).

RESULTS

OA cartilage exhibited elevated glycolysis and inflammation, while Songorine treatment significantly restored metabolic homeostasis and alleviated inflammation. In IL-1β-stimulated chondrocytes, Songorine suppressed glycolytic flux, reduced lactate production and histone H4K12 lactylation. Lactate-induced H4K12 lactylation promoted the transcription of pro-inflammatory genes and reinforced a PFKFB3-mediated positive feedback loop that sustained glycolysis and inflammation. SPR confirmed that Songorine directly binds to and inhibits PFKFB3, thereby disrupting this loop.

CONCLUSION

Songorine protects cartilage by directly targeting PFKFB3, thereby limiting glycolytic-driven lactate production, histone lactylation, and downstream inflammatory signaling. These findings uncover a novel glycolysis-lactylation-inflammation axis in OA and support Songorine as a promising metabolic modulator for OA therapy.