J Pineal Res. 2026 Sep;78(5):e70185. doi: 10.1111/jpi.70185.
ABSTRACT
Diabetic cardiomyopathy (DCM) is one of the most severe cardiovascular complications of diabetes mellitus (DM), yet effective treatment strategies remain lacking. Cellular senescence is a principal risk factor for multiple cardiovascular diseases, contributing significantly to cardiac dysfunction and disease progression. Melatonin, an endogenous hormone primarily secreted by the pineal gland, exerts cardioprotective effects against DCM. However, the underlying molecular mechanism remains incompletely understood, particularly whether melatonin ameliorates DCM by suppressing cardiomyocyte senescence. In this study, a streptozotocin (STZ)‑induced diabetic mouse model in vivo and an in vitro model of high‑glucose (HG)‑treated primary neonatal rat cardiomyocytes (NRCMs) were established. Melatonin ameliorated cardiac dysfunction in diabetic mice and alleviated the senescence phenotype in cardiomyocytes. Suppressing oxidative stress with the ROS scavenger N-acetylcysteine (NAC) effectively attenuated cardiomyocyte senescence, confirming the causal role of oxidative stress in senescence progression under HG conditions. Mechanistically, melatonin effectively upregulated the expression of melatonin receptor 1B (MT2), thereby activating the SIRT1/Nrf2 signaling pathway and promoting Nrf2 nuclear translocation. Notably, genetic ablation of Nrf2 in diabetic mice, as well as pharmacological inhibition of MT2, SIRT1, or Nrf2 in NRCMs, substantially abolished the protective effects of melatonin. Collectively, melatonin alleviates DCM by attenuating oxidative stress-induced cellular senescence through activation of the MT2/SIRT1/Nrf2 signaling pathway. These findings uncover a novel mechanism underlying the cardioprotective action of melatonin against DCM.
PMID:42745677 | DOI:10.1111/jpi.70185