ATOX1 alleviates radiation-induced cardiac injury by modulating AMPK/NRF2 to inhibit myocardial oxidative stress and mitochondrial dysfunction

Radiation-induced heart disease (RIHD) is a myocardial lesion caused by radiation exposure, and its pathogenesis is closely associated with oxidative stress. ATOX1 has been demonstrated to regulate oxidative stress, but its mechanism in RIHD remains unclear. We analyzed ATOX1 expression (Western blot [WB], RT-PCR), cardiomyocyte proliferation (MTT, IF), Apoptosis (TUNEL), AMPK signaling (WB, IF), and mitochondrial function (Reactive Oxygen Species [ROS], mPTP, JC-1) in vitro. A thoracic irradiation model was used in cardiomyocyte-specific ATOX1 knockout mice. Tissue analysis included IHC for ATOX1, KI-67, p-AMPK, and assessment of myocardial injury (ELISA, RT-PCR, and Masson's staining). Irradiation significantly reduced cardiomyocyte proliferation and increased Apoptosis. ATOX1 levels plummeted in irradiated cardiomyocytes, accompanied by mitochondrial ROS surges and disrupted integrity. Irradiation suppressed the AMPK/NRF2 axis, an effect reversed by ATOX1 overexpression. In mice, ATOX1 knockout exacerbated radiation-induced myocardial tissue damage. ATOX1 mitigates irradiation-induced cardiac damage by promoting mitochondrial and redox homeostasis in cardiomyocytes through AMPK/NRF2 pathway activation.