Zhang Lei, Kong Hong-Wei, Song Xu-Yu, Sheng Li-Song, Huang Na-Na, Liu Ying, Sun Rong
Basic Medical Research Institute, Integrated Traditional Chinese and Western Medicine Center, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China; National Administration of Traditional Chinese Medicine, High-level Key Disciplines of Traditional Chinese Medicine, Toxicology of Traditional Chinese Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China.
Phytomedicine. 2025 Sep;145:157037. doi: 10.1016/j.phymed.2025.157037. Epub 2025 Jul 6.
Cancer treatment may be hampered by doxorubicin (DOX)-induced cardiotoxicity (DIC), with limited therapeutic interventions currently available. PANoptosis, an inflammatory cell-death pathway, likely underlies DIC pathogenesis. The traditional Chinese medicine formulation Danggui Buxue decoction (DGBXD) enhances heart function, but the precise pharmacological mechanisms remain understudied.
This study aimed to investigate the effect of DGBXD on DIC and explore its underlying mechanisms.
Murine model of DIC and network pharmacology to predict potential targets. The model was established through intraperitoneal administration of DOX. Cardiac function and histopathological alterations were assessed using echocardiography, staining, and biochemical analyses. The active components in DGBXD-containing serum were characterized using mass spectrometry. Molecular docking simulations assessed their binding affinities with PANoptosis-related proteins. The expression of PANoptosis-associated proteins was evaluated in vivo and in vitro using western blotting, complemented by immunohistochemistry (animal tissues) and immunofluorescence (primary cardiomyocytes). The contribution of ZBP1 overexpression to the anti-PANoptotic effects of DGBXD was studied.
DGBXD administration significantly improved survival rates and cardiac function and attenuated myocardial damage in DOX-treated mice. Network pharmacology suggested that DGBXD modulates inflammation, oxidative stress, and modes of cellular death. Spectroscopy identified multiple bioactive components in DGBXD-containing serum. Molecular docking revealed that DGBXD constituents directly interacted with PANoptosis-related proteins. DGBXD suppressed DOX-induced PANoptosis in vivo and in vitro, as evidenced by the reduced levels of associated components. Overexpression of ZBP1 weakened this effect.
We highlight the clinical potential of DGBXD in ameliorating DIC, providing substantial evidence to support its development as a therapeutic agent for cardiovascular diseases.
阿霉素（DOX）诱导的心脏毒性（DIC）可能会阻碍癌症治疗，目前可用的治疗干预措施有限。全细胞凋亡是一种炎症性细胞死亡途径，可能是DIC发病机制的基础。中药配方当归补血汤（DGBXD）可增强心脏功能，但其确切的药理机制仍有待研究。
本研究旨在探讨DGBXD对DIC的影响并探索其潜在机制。
建立DIC小鼠模型并运用网络药理学预测潜在靶点。通过腹腔注射DOX建立模型。使用超声心动图、染色和生化分析评估心脏功能和组织病理学改变。采用质谱法鉴定含DGBXD血清中的活性成分。分子对接模拟评估它们与全细胞凋亡相关蛋白的结合亲和力。使用蛋白质印迹法在体内和体外评估全细胞凋亡相关蛋白的表达，并辅以免疫组织化学（动物组织）和免疫荧光（原代心肌细胞）。研究ZBP1过表达对DGBXD抗全细胞凋亡作用的影响。
给予DGBXD可显著提高DOX处理小鼠的存活率和心脏功能，并减轻心肌损伤。网络药理学表明，DGBXD可调节炎症、氧化应激和细胞死亡模式。光谱分析鉴定了含DGBXD血清中的多种生物活性成分。分子对接显示，DGBXD成分与全细胞凋亡相关蛋白直接相互作用。DGBXD在体内和体外均抑制DOX诱导的全细胞凋亡，相关成分水平降低证明了这一点。ZBP1过表达减弱了这种作用。
我们强调了DGBXD在改善DIC方面的临床潜力，为支持其作为心血管疾病治疗药物的开发提供了大量证据。
