Fig. 8. Schematic diagram depicting proposed Orai1–Drp1 signaling pathway in cardiomyocyte hypertrophy induced by HG.

HG stimulation induces upregulation of Orai1. Then, Orai1-mediated Ca²⁺ entry targets CnA to inhibit Drp1 phosphorylation at S637, inducing cardiac hypertrophy. Orai1-mediated Ca²⁺ entry also targets p-ERK1/2 to induce Drp1 phosphorylation at S616. Phosphorylation of Drp1 at S616 is increased, while phosphorylation of Drp1 at S637 is decreased, promoting mitochondrial fission and accelerating HG-induced cardiac hypertrophy. Inhibition of the Orai1–Drp1 signaling pathway could prevent cardiac hypertrophy induced by HG.