Therefore, the objective of this study was to evaluate the cytoprotective effect of H2S in primary cardiomyocyte cultures subjected to hyperglycemia, hypoxia–reoxygenation (HR), or both conditions, by assessing the PPAR-α/Keap1/Nrf2/p47phox/NOX4/p-eNOS/CAT/SOD and the PPAR-γ/PGC-1α/AMPK/GLUT4 signaling pathways. Here, NOS3 is linked to Hyperglycemia.