Identification of metabolic biomarkers in atrial fibrillation patients via the multi-omics strategy: the critical involvement of pyruvate kinase M2.

BACKGROUND

Atrial fibrillation (AF) is a common cardiac arrhythmia that contributes significantly to morbidity and mortality, with associated risks such as stroke and heart failure. This study aimed to identify novel biomarkers for AF progression using a multi-omics approach, combining proteomics and metabolomics, to gain a deeper understanding of AF pathophysiology and uncover potential diagnostic and therapeutic targets.

METHODS

We enrolled 39 participants, including 23 AF patients and 16 SR controls, and subjected their serum samples to tandem mass spectrometry-based proteomics and untargeted liquid chromatography-mass spectrometry-based metabolomics. Differential protein and metabolite expression were analyzed using bioinformatics tools, and the results were verified with in vitro assays.

RESULTS

A total of 19 differentially expressed proteins and 154 altered metabolites were identified in AF patients compared to controls. Among these, pyruvate kinase M2 (PKM2) stood out due to its significant correlation with glycolytic intermediates, such as lactate and phosphoenolpyruvate. Proteomic data revealed that PKM2 expression was significantly upgulated in AF patients. In vitro experiments using angiotensin II (Ang II)-treated cardiac fibroblasts confirmed that PKM2 is associated with fibrosis and cellular remodeling in AF. PKM2 knockdown significantly reduced fibroblast proliferation and α-SMA expression, attenuating fibrotic remodeling. The data also demonstrated that PKM2 regulates key metabolic and fibrotic pathways through its interaction with STAT3 signaling.

CONCLUSIONS

PKM2 is a key regulator of metabolic and fibrotic remodeling in AF and holds potential as both a biomarker for diagnosis and a therapeutic target.