Zheng Xin, Tang Xinyi, Xu Yinan, Zhu Haiyan, Zhong Lianwei, Chen Chen, Cui Jiajun, Zhou Jie
School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China.
School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China.
J Ethnopharmacol. 2025 Apr 9;345:119608. doi: 10.1016/j.jep.2025.119608. Epub 2025 Mar 8.
The seed of Aesculus wilsonii Rehd., also known as Suoluozi in China, is a traditional Chinese herb included in the Pharmacopoeia of China (2020). Sodium aescinate (SA) is derived from the Aesculus wilsonii Rehd.'s seeds and is extensively used in clinical practice.
The study investigated the involvement of the Nrf2/CTH pathway in SA-induced hepatotoxicity and explored potential strategies for alleviating SA-induced liver damage.
The ICR mice and AML12 mouse hepatocytes were exposed to SA. The levels of Fe, cysteine (Cys), glutathione (GSH), hydrogen sulfide (HS), ROS, lipid peroxides and caspase-3 activity were assessed. The effects of SA on signaling pathways related to ferroptosis and apoptosis were examined. Furthermore, genetic modification or agonists of Nrf2 and CTH were co-treated with SA.
SA triggered ferroptosis and apoptosis in AML12 cells and mouse livers, characterized by a decline in Cys, GSH, and HS levels, as well as accumulation of Fe, ROS and lipid peroxides, mitochondrial dysfunction, and chromatin condensation. SA decreased Nrf2, CTH, and Bcl-2 levels, elevated Bax levels, and activated caspase-9/3. Overexpression of Nrf2 or CTH, or NAC supplementation alleviated SA-induced ferroptosis by upregulating Cys and GSH levels. Overexpression of Nrf2 or CTH, or NaHS supplementation increased HS levels, which reduced the interaction between p616-Drp1 and VDAC1 by enhancing Drp1 S-sulfenylation, thereby alleviating SA-induced mitochondrial-dependent apoptosis. Furthermore, DMF or Met mitigated SA-induced hepatotoxicity by activating the Nrf2/CTH pathway.
SA triggers oxidative stress, mitochondrial dysfunction, apoptosis, and ferroptosis, ultimately leading to liver damage by suppressing the Nrf2/CTH pathway.
天师栗种子，在中国也被称为娑罗子，是《中国药典》（2020年版）收录的一味传统中药。七叶皂苷钠（SA）源自天师栗种子，在临床实践中被广泛应用。
本研究调查了Nrf2/CTH通路在SA诱导的肝毒性中的作用，并探索减轻SA诱导的肝损伤的潜在策略。
将ICR小鼠和AML12小鼠肝细胞暴露于SA中。评估铁（Fe）、半胱氨酸（Cys）、谷胱甘肽（GSH）、硫化氢（HS）、活性氧（ROS）、脂质过氧化物水平及半胱天冬酶-3（caspase-3）活性。检测SA对与铁死亡和细胞凋亡相关信号通路的影响。此外，将Nrf2和CTH的基因修饰物或激动剂与SA共同处理。
SA在AML12细胞和小鼠肝脏中引发铁死亡和细胞凋亡，其特征为Cys、GSH和HS水平下降，以及Fe、ROS和脂质过氧化物积累、线粒体功能障碍和染色质凝聚。SA降低了Nrf2、CTH和Bcl-2水平，升高了Bax水平，并激活了caspase-9/3。Nrf2或CTH过表达，或补充NAC，通过上调Cys和GSH水平减轻了SA诱导的铁死亡。Nrf2或CTH过表达，或补充NaHS增加了HS水平，通过增强Drp1 S-亚磺酰化减少了p616-Drp1与VDAC1之间的相互作用，从而减轻了SA诱导的线粒体依赖性细胞凋亡。此外，二甲基富马酸（DMF）或蛋氨酸（Met）通过激活Nrf2/CTH通路减轻了SA诱导的肝毒性。
SA通过抑制Nrf2/CTH通路引发氧化应激、线粒体功能障碍、细胞凋亡和铁死亡，最终导致肝损伤。
