Loss of eIF3m aggravates myocardial ischemia/reperfusion injury via enhancing nitrative damage and inhibiting glycolytic reprogramming.

The reprogramming of myocardial energy metabolism is critical for cardiac repair after ischemia/reperfusion (I/R) injury, yet the upstream translational control mechanisms remain elusive. Here, through multi-omics analysis of human failing hearts, we identify the mRNA regulator eIF3m as an essential factor for maintaining cardiac glycolytic flux post-I/R. We show that eIF3m, independently of the canonical eIF3 complex, stabilizes Mt2 and related stress-response mRNAs, ultimately protecting the key glycolytic activator Pfkfb3. Loss of eIF3m impairs the heart's adaptive shift toward utilizing glycolysis for energy, leading to contractile dysfunction. Mechanistically, eIF3m deficiency exacerbates excessive nitro-oxidative stress, which damages and inactivates the key glycolytic enzyme Pfkfb3. This damage is counteracted by the metallothionein Mt2, a direct binding partner of eIF3m. Our findings reveal the eIF3m-Mt2 axis as a novel translational checkpoint that governs metabolic reprogramming and nitrative stress resistance in the injured heart, nominating it as a potential therapeutic target for myocardial I/R injury.