Rescuing cells from stress damage emerges a potential therapeutic strategy to combat myocardial infarction.Protocatechuic aldehyde(PCA)is a major phenolic acid in Chinese herb Danshen(SSalvia miltiorrhiza root).This study investigated whether PCA regulated nuclear pyruvate kinase iso-form M2(PKM2)function to protect cardiomyocytes.In rats subjected to isoprenaline,PCA attenuated heart injury and protected cardiomyocytes from apoptosis.Through DARTS and CETSA assays,we iden-tified that PCA bound and promoted PKM2 nuclear translocation in cardiomyocytes exposed to oxygen/glucose deprivation(OGD).In the nucleus,PCA increased the binding of PKM2 to β-catenin via preser-ving PKM2 acetylation,and the complex,in cooperation with T-cell factor 4(TCF4),was required for transcriptional induction of genes encoding anti-apoptotic proteins,contributing to rescuing cardiomyo-cyte survival.In addition,PCA ameliorated mitochondrial dysfunction and prevented mitochondrial apoptosis dependent on PKM2.Consistently,PCA increased the binding of PKM2 to β-catenin,improved heart contractive function,normalized heart structure and attenuated oxidative damage in mice subjected to artery ligation,but the protective effects were lost in Pkm2-deficient heart.Together,we showed that PCA regulated nuclear PKM2 function to rescue cardiomyocyte survival via β-catenin/TCF4 signaling cascade,suggesting the potential of pharmacological intervention of PKM2 shuttle to protect the heart.