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In addition, using CMSPkm2 modRNA, our novel CM-targeted strategy, following acute or chronic MI resulted in increased CM cell division, enhanced cardiac function and improved long-term survival. We mechanistically show that Pkm2 regulates the CM cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin. Conclusions We demonstrate that Pkm2 is an important intrinsic regulator of the CM cell cycle and oxidative stress and highlight its therapeutic potential using CMSPkm2 modRNA as a gene delivery platform.Hype