<b><i>Introduction:</i></b> Moderate hydrogen peroxide postconditioning (H<sub>2</sub>O<sub>2</sub>PoC) activates signal transducer and activator of transcription 3 (STAT3) to alleviate mitochondrial calcium overload during cardiac ischemia/reperfusion (I/R). However, the initial time window of STAT3-induced calcium hemostasis, the production of reactive oxygen species (ROS) and adenosine triphosphate (ATP) in H<sub>2</sub>O<sub>2</sub>PoC, and its regulated mechanism remain unknown. This study aimed to investigate H<sub>2</sub>O<sub>2</sub>PoC-induced homeostasis of calcium, ROS and ATP, and the role of STAT3 in the regulation. <b><i>Methods:</i></b> Isolated rat cardiomyocytes were exposed to H<sub>2</sub>O<sub>2</sub>PoC and Janus kinase 2 (JAK2)/STAT3 inhibitor AG490 during I/R. Ca<sup>2+</sup> transients, cell contraction, intracellular calcium concentration, ROS production, ATP contents, phosphorylation of STAT3, gene and protein expression of manganese superoxide dismutase (MnSOD), metallothionein 1 (MT1) and metallothionein 2 (MT2), as well as activities of mitochondrial complex I and complex II were detected. <b><i>Results:</i></b> Moderate H<sub>2</sub>O<sub>2</sub>PoC improved post-ischemic Ca<sup>2+</sup> transients and cell contraction recovery as well as alleviated cytosolic and mitochondrial calcium overload, which were abrogated by AG490 in rat cardiomyocytes. Moderate H<sub>2</sub>O<sub>2</sub>PoC increased ROS production and rate of ROS production at early reperfusion in rat I/R cardiomyocytes, and this phenomenon was also abrogated by AG490. Notably, the expression of phosphorylated nuclear STAT3; gene and protein expression of MnSOD, MT1, and MT2; and activities of mitochondrial complex I and complex II were upregulated by moderate H<sub>2</sub>O<sub>2</sub>PoC but downregulated by AG490. <b><i>Conclusion:</i></b> These findings indicated that the cardioprotection of moderate H<sub>2</sub>O<sub>2</sub>PoC against cardiac I/R could be associated with activated STAT3 at early reperfusion to maintain calcium, ROS, and ATP homeostasis in rat cardiomyocytes.
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