Morusin attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis via dual activation of the Nrf2/HO-1 pathway and mTORC1-dependent GPX4 synthesis

Myocardial ischemia/reperfusion injury (MIRI) involves exacerbated oxidative stress and Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation. Morusin, a flavonoid from Morus alba, exhibits antioxidant properties, but its role in MIRI remains unclear. This study investigated morusin's cardioprotective effects and mechanisms in in vitro and in vivo MIRI models. In oxygen-glucose deprivation/reoxygenation (OGD/R)-treated H9c2 cells and murine I/R injury models, morusin significantly improved cell viability, reduced oxidative stress markers (ROS, MDA, 4-HNE), and suppressed inflammatory cytokine release. Mechanistically, morusin stabilized nuclear factor erythroid 2-related factor 2 (Nrf2) by disrupting its interaction with Keap1, thereby activating the Nrf2/HO-1 antioxidant axis. This activation enhanced Glutathione Peroxidase 4 (GPX4) transcription, a key Ferroptosis suppressor. Additionally, morusin promoted GPX4 protein synthesis via mTORC1 signaling, evidenced by increased phosphorylation of S6K and 4EBP1. Genetic or pharmacological inhibition of Nrf2, HO-1, or mTORC1 abolished morusin's protective effects, confirming their critical roles. In vivo, morusin reduced myocardial infarct size, preserved mitochondrial integrity, and lowered serum cardiac injury markers (LDH, CK-MB) in I/R mice. These findings reveal that morusin mitigates MIRI by dual modulation of Ferroptosis through Nrf2/HO-1-mediated antioxidative responses and mTORC1-dependent GPX4 upregulation. This study highlights morusin's therapeutic potential for ischemic heart diseases, offering novel insights into targeting Ferroptosis for cardioprotection.

Ferroptosis; GPX4; Ischemia/reperfusion; Morusin; Nrf2.