Brown Adipocyte Sheets Alleviate Myocardial Ischemia–Reperfusion Injury Through NRG4–ErbB4–Dependent Ferroptosis Inhibition

ABSTRACT Myocardial ischemia–reperfusion (I/R) injury causes cardiomyocyte death and cardiac dysfunction in part through ferroptosis. Brown adipocytes (BAs) have emerged as endocrine regulators with cardioprotective potential, yet their involvement in ferroptosis modulation during I/R injury remains unclear. Here, we engineered BA sheets and transplanted them onto the ischemic myocardium in a rat I/R model to evaluate therapeutic efficacy. BA sheets transplantation significantly improved cardiac function, reduced infarct size and fibrosis, and mitigated adverse remodeling while enhancing angiogenesis. In vitro, conditioned medium derived from BA sheets promoted cardiomyocyte survival, preserved contractile performance, and inhibited apoptosis and ferroptosis under hypoxia/reoxygenation stress. Mechanistically, these effects were mediated by the activation of the NRG4–ErbB4 axis and its downstream PI3K/AKT and NRF2/HO‐1 antioxidant signaling pathways. Our findings demonstrate that engineered BA sheets exert potent cardioprotection against myocardial I/R injury by suppressing ferroptosis in an NRG4–ErbB4–dependent manner, supporting their promise as a therapeutic strategy for ischemic heart disease.