The current research revealed, for the first time to the authors’ knowledge, the alleviating role of adropin and/or Tirze on PCOS-associated cardiometabolic abnormalities, with superiority of combination treatment, mostly mediated via modulating the cardiac Akt/GSK3β signaling pathway, which consequently ameliorated oxidative damage, abrogated the inflammatory processes, and modulated ER stress and associated apoptosis. This evidence concerns the gene AKT1 and polycystic ovary syndrome.