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

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 IGF...

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Published in:Journal of translational medicine Vol. 23; no. 1; pp. 1080 - 17
Main Authors: Yang, Chenguang, Meng, Xuyang, Xia, Chenxi, Sun, Youjing, Ren, Yirong, Wang, Jun, Li, Yi, Wang, Xiang
Format: Journal Article
Language:English
Published: London BioMed Central 13.10.2025
BioMed Central Ltd
BMC
Subjects:
Aerobic exercise
Aerobic exercises
Animals
Binding proteins
Biomedical and Life Sciences
Biomedicine
Cardiomyocyte
Cardiomyopathy
Cardiovascular
Care and treatment
Causes of
Cell death
Complications and side effects
Development and progression
Ferroptosis
Health aspects
Heart diseases
IGFBP2
Insulin-Like Growth Factor Binding Protein 2 - metabolism
Iron in the body
Ischemia/reperfusion injury
Male
Medicine/Public Health
Metabolic and Lipoprotein Translation
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial ischemia
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - pathology
Myocardial Reperfusion Injury - physiopathology
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Physical Conditioning, Animal
Physiological aspects
Reperfusion injury
Sirtuin 1 - metabolism
China
Ferroptosis
Ischemia/reperfusion injury
Cardiomyocyte
IGFBP2
Aerobic exercise
ISSN:1479-5876, 1479-5876
Online Access:Get full text
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Summary: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 exercise on cardiomyocyte ferroptosis ( p < 0.001). SIRT1 activation inhibited ferroptosis in cardiomyocytes exposed to H/R by downregulating TXNIP expression, upregulating TRX expression, and increasing TXNIP/TRX binding ( p < 0.001). Inhibition of TXNIP suppressed ferroptosis following H/R ( p < 0.001). Conclusion Aerobic exercise-induced circulating IGFBP2 directly interacts with IGF-1R, leading to increased activation of SIRT1 and reduced levels of free TXNIP, thus inhibiting cardiomyocyte ferroptosis in cardiac I/R injury. Graphical abstract
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ISSN:1479-5876
1479-5876
DOI:10.1186/s12967-025-06982-6