Li Qiyang, Zhang Shangzu, Li Yangyang, Yao Ning, Feng Yuye, Yang Gengqiang, Wang Yutong, Dai Sichao, Cheng Shuai, Zhou Ting, Wang Xin, Zhang Liying
Provincial Key Laboratory of Molecular Medicine and Prevention Research of Major Diseases, Gansu University of Chinese Medicine, Lanzhou 730000, China.
Hubei University of Chinese Medicine, Wuhan 430065, China.
Phytomedicine. 2025 Oct;146:157135. doi: 10.1016/j.phymed.2025.157135. Epub 2025 Aug 14.
Radiation-induced heart disease (RIHD) has emerged as a critical complication compromising the long-term survival of cancer patients undergoing radiotherapy. Although targeting myocardial energy metabolism is a promising therapeutic strategy for cardiovascular diseases, the molecular mechanisms underlying ionizing radiation-induced cardiomyocyte metabolic dysregulation and subsequent cardiac injury remain unclear.
This study aims to explore the mechanism by which Astragaloside IV (AS-Ⅳ) alleviates RIHD through the regulation of energy metabolism.
This study established mouse and cellular models of radiation-induced heart injury to investigate the effects of X-ray radiation on energy metabolism in the hearts of C57BL/6 mice and in cardiomyocyte cell lines (AC16 and H9C2). By integrating untargeted metabolomics with experimental validation, we elucidated the pharmacological effects and molecular mechanisms of the HIF-1α inhibitor (PX-478) and AS-IV intervention in mouse heart tissue and cardiomyocytes.
In vitro experiments demonstrated that X-rays at doses of 6 Gy and above induced damage and abnormal energy metabolism in H9C2 and AC16 cardiomyocytes at 24, 48, and 72 h, respectively. These abnormalities were primarily characterized by inhibited cell proliferation, increased apoptosis, decreased ATP content, and elevated lactate and lipid accumulation. These phenomena may be associated with the abnormal activation of the HIF-1α/PPARγ signaling pathway. Additionally, AS-IV effectively mitigated radiation-induced cardiomyocyte injury by regulating HIF-1α/PPARγ-mediated glycolysis and triglyceride synthesis metabolism, as well as by alleviating mitochondrial damage.
Abnormal activation of the HIF-1α/PPARγ axis may represent a potential mechanism underlying X-ray-induced abnormalities in myocardial energy metabolism and cellular damage. Furthermore, AS-IV has the potential to alleviate radiocardiac injury by modulating energy metabolism and restoring mitochondrial function.
放射性心脏病（RIHD）已成为影响接受放疗的癌症患者长期生存的关键并发症。尽管针对心肌能量代谢是心血管疾病的一种有前景的治疗策略，但电离辐射诱导心肌细胞代谢失调及随后心脏损伤的分子机制仍不清楚。
本研究旨在探讨黄芪甲苷（AS-Ⅳ）通过调节能量代谢减轻放射性心脏病的机制。
本研究建立了辐射诱导心脏损伤的小鼠和细胞模型，以研究X射线辐射对C57BL/6小鼠心脏和心肌细胞系（AC16和H9C2）能量代谢的影响。通过将非靶向代谢组学与实验验证相结合，我们阐明了HIF-1α抑制剂（PX-478）和AS-Ⅳ干预对小鼠心脏组织和心肌细胞的药理作用及分子机制。
体外实验表明，6 Gy及以上剂量的X射线分别在24、48和72 h诱导H9C2和AC16心肌细胞损伤及能量代谢异常。这些异常主要表现为细胞增殖受抑制、凋亡增加、ATP含量降低以及乳酸和脂质积累升高。这些现象可能与HIF-1α/PPARγ信号通路的异常激活有关。此外，AS-Ⅳ通过调节HIF-1α/PPARγ介导的糖酵解和甘油三酯合成代谢，以及减轻线粒体损伤，有效减轻了辐射诱导的心肌细胞损伤。
HIF-1α/PPARγ轴的异常激活可能是X射线诱导心肌能量代谢异常和细胞损伤的潜在机制。此外，AS-Ⅳ有潜力通过调节能量代谢和恢复线粒体功能来减轻放射性心脏损伤。
