Han Quancheng, Guo Yonghong, Yu Yiding, Shi Jingle, Yuan Huajing, Yu Hui, Liu Xiujuan, Xue Yitao, Li Yan
Shandong University of Traditional Chinese Medicine.
Affiliated Hospital of Shandong University of Traditional Chinese Medicine.
J Ethnopharmacol. 2026 Jan 30;355(Pt B):120037. doi: 10.1016/j.jep.2025.120037. Epub 2025 Sep 10.
Heart failure (HF), the terminal stage of various cardiovascular diseases, represents a significant threat to global health. Fuxin Decoction (FXD), a classical Traditional Chinese Medicine (TCM) formula, has demonstrated therapeutic efficacy in HF treatment. However, its bioactive components and precise mechanisms remain to be elucidated.
This study aimed to elucidate the material basis and mechanistic pathways underlying FXD's therapeutic effects on HF, thereby proposing a novel, safe, and effective treatment strategy.
First, UPLC-Q/TOF-MS was employed to identify active compounds in FXD. Subsequently, network pharmacology analysis was conducted to explore FXD's regulatory effects on ferroptosis and the Nrf2/SLC7A11/GPX4 signaling pathway. A rat HF model was established, and FXD's therapeutic effects were assessed via echocardiography and serum NT-proBNP measurement. Histopathological evaluation was performed using H&E and Masson staining, while mitochondrial ultrastructural changes were examined via transmission electron microscopy (TEM). Additionally, ferroptosis-related markers (Fe, MDA, GSH, and GPX4) were quantified in myocardial tissue. Finally, RNA interference-mediated Nrf2 silencing was applied to investigate FXD's cardioprotective effects and ferroptosis modulation in H9c2 cardiomyocytes.
A total of 62 bioactive compounds were identified in FXD. Network pharmacology analysis revealed, for the first time, FXD's potential modulation of ferroptosis and the Nrf2/SLC7A11/GPX4 pathway. In vivo, FXD significantly improved cardiac function in HF rats, reduced NT-proBNP levels, and attenuated cardiomyocyte damage. FXD exerted potent anti-ferroptotic effects, evidenced by mitigated mitochondrial injury, decreased Fe and MDA levels, and elevated GSH and GPX4 activity. Furthermore, FXD upregulated key proteins in the Nrf2/SLC7A11/GPX4 pathway. Crucially, Nrf2 silencing partially abolished FXD's cardioprotection, confirming Nrf2's central role in mediating FXD's anti-ferroptotic effects.
FXD is a safe and effective therapeutic agent for heart failure, and its mechanism of action may be closely related to ferroptosis mediated by the Nrf2/SLC7A11/GPX4 signaling pathway.
心力衰竭（HF）是各种心血管疾病的终末期，对全球健康构成重大威胁。复心汤（FXD）是一种经典的中药配方，已在HF治疗中显示出治疗效果。然而，其生物活性成分和确切机制仍有待阐明。
本研究旨在阐明FXD对HF治疗作用的物质基础和作用机制，从而提出一种新颖、安全、有效的治疗策略。
首先，采用超高效液相色谱-四极杆/飞行时间质谱（UPLC-Q/TOF-MS）鉴定FXD中的活性成分。随后，进行网络药理学分析，以探讨FXD对铁死亡和Nrf2/SLC7A11/GPX4信号通路的调节作用。建立大鼠HF模型，并通过超声心动图和血清NT-proBNP测量评估FXD的治疗效果。使用苏木精-伊红（H&E）和Masson染色进行组织病理学评估，同时通过透射电子显微镜（TEM）检查线粒体超微结构变化。此外，对心肌组织中的铁死亡相关标志物（铁、丙二醛、谷胱甘肽和谷胱甘肽过氧化物酶4）进行定量分析。最后，应用RNA干扰介导的Nrf2沉默来研究FXD对H9c2心肌细胞的心脏保护作用和铁死亡调节作用。
在FXD中总共鉴定出62种生物活性成分。网络药理学分析首次揭示了FXD对铁死亡和Nrf2/SLC7A11/GPX4通路的潜在调节作用。在体内，FXD显著改善了HF大鼠的心脏功能，降低了NT-proBNP水平，并减轻了心肌细胞损伤。FXD发挥了强大的抗铁死亡作用，表现为线粒体损伤减轻、铁和丙二醛水平降低以及谷胱甘肽和谷胱甘肽过氧化物酶4活性升高。此外，FXD上调了Nrf2/SLC7A11/GPX4通路中的关键蛋白。至关重要的是，Nrf2沉默部分消除了FXD的心脏保护作用，证实了Nrf2在介导FXD抗铁死亡作用中的核心作用。
FXD是一种治疗心力衰竭的安全有效药物，其作用机制可能与Nrf2/SLC7A11/GPX4信号通路介导的铁死亡密切相关。
