IGFBP2 plays a key role in aerobic exercise-mediated inhibition of ferroptosis in cardiac ischemia/reperfusion (I/R) injury

作者：Chenguang Yang, Xuyang Meng, Chenxi Xia, Youjing Sun, Yirong Ren, Jun Wang, Yi Li, Xiang Wang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06982-6 · 被引用次数：2 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、GDF15 and Related Biomarkers

BACKGROUND: Ferroptosis is an important mechanism underlying cardiac ischemia/reperfusion (I/R) injury. However, the specific molecular mechanisms by which aerobic exercise alleviates cardiac I/R injury and inhibits ferroptosis remain unclear. METHODS: In this study, we investigated the effects of IGFBP2 on aerobic exercise-mediated protection of cardiac function following I/R and its influence on ferroptosis in cardiomyocytes and SIRT1 activation. Wild-type (WT) or IGFBP2 knockout (IGFBP2_KO) C57BL/6J mice with I/R injury were subjected to aerobic exercise intervention, and cardiomyocytes exposed to hypoxia/reoxygenation (H/R) were treated with IGFBP2. We explored the role of IGF-1R in IGFBP2-mediated cardiac protection using IGF-1R conditional knockout (IGF-1R_CKO) mice subjected to aerobic exercise intervention and cardiomyocytes exposed to H/R and incubated with IGFBP2 and IGF-1R silenced via adenoviral vector (ADV) transfection. The effects of SIRT1 and TXNIP/TRX on ferroptosis in cardiomyocytes exposed to H/R were also examined using SIRT1 inhibitors, SIRT1 agonists, and adenovirus transfection to modulate TXNIP expression levels. RESULTS: Aerobic exercise increased circulating IGFBP2 levels in mice, inhibited ferroptosis in cardiomyocytes, and protected cardiac function following I/R (p < 0.001). IGFBP2 suppressed ferroptosis in cardiomyocytes subjected to H/R and enhanced SIRT1 activation (p < 0.001). IGF-1R_CKO abrogated the inhibitory effects of IGFBP2 and aerobic e...