S-Nitrosylation of Pyruvate Kinase Isoform 2 Drives Cardiac Fibrosis by Promoting Mitochondrial Fission.
Summary
This study identifies S-nitrosylated PKM2 as a fibroblast-specific driver of cardiac fibrosis via gelsolin-dependent promotion of mitochondrial fission. Pharmacologic activation of PKM2 (TEPP-46 and the FDA-approved mitapivat) reversed mitochondrial fission and attenuated fibrosis across preclinical models, suggesting repurposing potential for antifibrotic therapy.
Key Findings
- S-nitrosylation of PKM2 (Cys49/326) is elevated in cardiac fibroblasts from human HF and multiple fibrosis models.
- SNO-PKM2 reduces PKM2 activity/tetramerization and drives gelsolin-dependent mitochondrial fission, promoting fibroblast activation and fibrosis.
- PKM2 activators (TEPP-46, mitapivat) attenuate mitochondrial fission and cardiac fibrosis in preclinical models.
Clinical Implications
PKM2 activation may represent a novel antifibrotic strategy for heart failure; mitapivat could be evaluated in early-phase cardiofibrosis trials with biomarker-guided selection (e.g., SNO-PKM2 signature).
Why It Matters
Reveals a previously unrecognized redox-metabolic mechanism of fibrosis and provides an actionable, human-approved drug (mitapivat) as a translational candidate. This bridges mechanistic discovery with therapeutic intervention in a major unmet need.
Limitations
- Preclinical study; human sample sizes and clinical generalizability are not defined
- Dosing, safety, and cardiac-specific delivery of PKM2 activators for antifibrotic purposes require clinical evaluation
Future Directions
Early-phase trials testing mitapivat/PKM2 activation in HF with fibrosis; develop fibroblast-targeted delivery; validate SNO-PKM2 as a biomarker; explore combination with RAAS/SGTL2i therapy.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence using animal models and human tissues; hypothesis-generating for therapy.
- Study Design
- OTHER