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Pyruvate kinase M2 is elevated in systemic sclerosis and plays a role in its pathogenesis
Thomas Steadman1, Steven O'Reilly1
1Biosciences Department, Durham University, Durham, United Kingdom.
Frontiers in Immunology
|August 7, 2026
Summary
Pyruvate kinase M2 (PKM2) drives systemic sclerosis (SSc) fibroblast activation through glycolysis. Targeting PKM2 or lactate generation may offer new therapeutic avenues for this fibrotic skin disease.
Area of Science:
- Biochemistry
- Immunology
- Dermatology
Background:
- Systemic sclerosis (SSc) is an autoimmune fibrotic skin disease characterized by immune activation and fibrosis.
- Fibroblasts are central to SSc pathogenesis, differentiating into myofibroblasts, but the drivers are unclear.
- Metabolic alterations, including in glycolysis, are increasingly recognized in fibrotic diseases.
Purpose of the Study:
- To investigate the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in systemic sclerosis (SSc).
Main Methods:
- Analyzed serum and fibroblast PKM2 levels in SSc patients and controls using ELISA.
- Treated healthy fibroblasts with TGF-β1 to assess PKM2 expression and modulated PKM2 activity.
- Evaluated collagen, extracellular matrix (ECM) regulators, metabolic activity, and histone lactylation.
- Utilized Seahorse assays, pharmacological inhibitors, and chromatin immunoprecipitation.
Main Results:
- Elevated PKM2 was found in SSc patient serum and fibroblasts, inducible by TGF-β1.
- PKM2 promoted glycolysis, leading to increased lactate production and subsequent collagen synthesis via histone H3K18 lactylation.
- Pharmacological blockade of PKM2 dimerization reduced ECM production and histone lactylation.
- Lactate-induced collagen synthesis was partially mediated by HIF-1α.
Conclusions:
- PKM2-driven glycolysis activates fibroblasts in SSc through metabolic and epigenetic modifications.
- Targeting PKM2 tetramerization or lactate generation presents a potential therapeutic strategy for SSc.
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