MAT2A promotes atherosclerotic plaque vulnerability by mediating epigenetic reprogramming of macrophages.

Summary

Monocyte methionine metabolism, driven by MAT2A, primes proinflammatory and migratory programs via H3K4me3 and is linked to OCT-defined vulnerable plaque and 5-year prognosis. Genetic and pharmacologic suppression of MAT2A, or methionine restriction, dampened macrophage activation and reduced plaque vulnerability, with norepinephrine–mTOR–c-MYC signaling upstream of MAT2A.

Key Findings

• Monocyte methionine metabolism correlated with OCT-defined thin-cap fibroatheroma in humans.
• MAT2A was upregulated in atherosclerosis and enriched H3K4me3 at inflammatory/migratory gene promoters.
• Myeloid-specific MAT2A deletion, pharmacologic inhibition, or low-methionine diet reduced macrophage inflammation/migration and plaque vulnerability.
• Norepinephrine activated the mTOR–c-MYC axis to upregulate MAT2A; the NE–methionine metabolism combination associated with TCFA and 5-year prognosis.

Clinical Implications

While not yet practice-changing, MAT2A and methionine metabolism emerge as therapeutic targets to stabilize plaques, and norepinephrine signaling may be a modifiable upstream driver. These findings support biomarker development and early-phase trials of MAT2A inhibitors or dietary methionine modulation.

Limitations

• Translational gap: mechanistic findings require clinical trials to test MAT2A-targeted interventions
• Human associations are observational and may be confounded; OCT-defined vulnerability is a surrogate rather than clinical events

Future Directions

Develop selective MAT2A inhibitors and test methionine restriction strategies; evaluate beta-adrenergic modulation of MAT2A signaling; validate biomarkers linking methionine flux to plaque instability and outcomes.