中医药学报

益气活血利水汤调控Nrf2/GPX4信号通路抑制铁死亡改善肝纤维化大鼠的机制研究

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刘晶晶 ¹ , 周小琦 ² , 王璐 ³ , 童丽君 ¹ , 戴琦 ³^,^*

中医药学报 | 实验研究 2026,54(6): 18-24

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中医药学报 |实验研究 2026 , 54 (6) : 18 -24

益气活血利水汤调控Nrf2/GPX4信号通路抑制铁死亡改善肝纤维化大鼠的机制研究

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刘晶晶¹, 周小琦², 王璐³, 童丽君¹, 戴琦³^,^*

作者信息

^1.江西中医药大学，江西南昌 330004

^2.广州中医药大学，广东广州 510405

^3.江西中医药大学附属医院，江西南昌 330006

通讯作者:

^* 戴琦（1970-），女，硕士，副教授，主任中医师，从事肝胆脾胃病相关研究。

作者简介:

刘晶晶（1996-），女，硕士，从事肝胆脾胃病相关研究。

Mechanism of Yiqi Huoxue Lishui Decoction Regulating Nrf2/GPX4 Signaling Pathway to Inhibit Ferroptosis and Improve Liver Fibrosis in Rats

Jingjing LIU¹, Xiaoqi ZHOU², Lu WANG³, Lijun TONG¹, Qi DAI³^,^*

Affiliations

^1.Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

^2.Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, China

^3.The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China

出版时间: 2026-06-20 doi: 10.19664/j.cnki.1002-2392.260113

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摘要

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目的：

研究益气活血利水汤通过激活核因子-E2相关因子2（Nrf2）/胱甘肽过氧化物酶4 （GPX4）信号通路抑制肝细胞铁死亡改善肝纤维化（HF）大鼠的作用机制。

方法：

40只SD大鼠随机分为5组，分别为对照组（Control）、模型组（Model）、中药组（TCM）、中药+铁死亡抑制剂组（TCM + Fer-1）、中药+铁死亡抑制剂+自噬抑制剂组（TCM + Fer-1 + 3-MA），每组8只。造模采用50%四氯化碳（CCl₄）腹腔注射（1.5 mL/kg），每周2次，持续4周。治疗各组给予相应药物，其中益气活血利水汤通过灌胃给药（2 mL/100 g），铁死亡抑制剂（Fer-1，1 mg/kg）和细胞自噬抑制剂（3-MA，15 mg/kg）通过腹腔注射给药，每日1次，持续4周，其余组给予等量生理盐水代替。HE和Masson染色观察肝组织病理变化；检测血清中天门冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、肿瘤坏死因子α （TNF-α）、超氧化物歧化酶（SOD）、丙二醛（MDA）以及血清和肝组织Fe²⁺含量；蛋白免疫印迹法（WB）检测肝组织GPX4、Nrf2、溶质载体家族7成员11（SLC7A11）、转铁蛋白受体1（TFR1）、苄氯素1 （Beclin-1）、LC3Ⅱ/LC3Ⅰ表达情况；实时荧光定量聚合酶链式反应（qPCR）检测Nrf2、GPX4的mRNA表达情况。

结果：

与Control比较，Model肝组织出现大量脂肪性病变，纤维化明显，胶原容积显著上升，ASL、ALT、MDA、TNF-α、Fe²⁺的含量显著升高（P < 0.05），SOD含量降低（P < 0.05），GPX4、Nrf2、SLC7A11蛋白表达升高（P < 0.05），TFR1、Beclin-1蛋白表达升高（P < 0.05），GPX4、Nrf2的mRNA表达显著降低（P < 0.05）；与Model比较，给药干预各组肝脏组织病理显著改善，ASL、ALT、MDA、TNF-α、血清及肝脏Fe²⁺含量、TFR1和Bclin-1蛋白表达均不同程度降低（P < 0.05）；SOD含量、GPX4和Nrf2蛋白表达和mRNA表达、SLC7A11的蛋白表达水平呈不同程度上升（P < 0.05），其中LC3Ⅱ/LC3Ⅰ蛋白表达差异无统计学意义（P > 0.05）。

结论：

益气活血利水汤通过调控Nrf2/GPX4信号通路抑制铁死亡改善肝纤维化大鼠。

关键词

肝纤维化 / 益气活血利水汤 / 铁死亡 / Nrf2/GPX4 / 细胞自噬

Abstract

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Objective:

To investigate the mechanism by which Yiqi Huoxue Lishui Decoction ameliorates hepatic fibrosis (HF) in rats by inhibiting hepatocyte ferroptosis via activation of the nuclear factor-E2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway.

Method:

Forty Sprague-Dawley (SD) rats were randomly divided into five groups (n =8 per group) : the control group (Control), model group (Model), traditional Chinese medicine group (TCM), traditional Chinese medicine + ferroptosis inhibitor group (TCM + Fer-1), and traditional Chinese medicine + ferroptosis inhibitor + autophagy inhibitor group (TCM + Fer-1 + 3-MA). The model was established by intraperitoneal injection of a 50% carbon tetrachloride (CCl₄) solution (1.5 mL/kg), administered twice weekly for 4 weeks. Treatment groups received their respective interventions: the Yiqi Huoxue Lishui Decoction was administered via oral gavage (2 mL/100 g), while the ferroptosis inhibitor Ferrostatin-1(Fer-1) (1 mg/kg) and the autophagy inhibitor 3-Methyladenine (3-MA) (15 mg/kg) were administered via intraperitoneal injection. All administrations were performed once daily for 4 weeks, while the other groups were given an equivalent volume of normal saline. Hepatic histopathological changes were evaluated using hematoxylin-eosin (HE) and Masson staining. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), malondialdehyde (MDA), and Fe²⁺ content in serum and liver tissue were measured. Western blot (WB) was employed to assess protein expression of GPX4, Nrf2, solute carrier family 7 member 11 (SLC7A11), transferring receptor 1 (TFR1), Beclin-1, and the LC3 II/I ratio. Quantitative real-time polymerase chain reaction (qPCR) was utilized to determine mRNA expression levels of Nrf2 and GPX4.

Results:

Compared with the Control group, the Model group exhibited severe hepatic steatosis, significant fibrosis, elevated collagen deposition, increased serum AST, ALT, MDA, TNF-α, and Fe²⁺ levels, and reduced SOD activity (P < 0.05). Protein expression of GPX4, Nrf2, and SLC7A11 was upregulated, while TFR1 and Beclin-1 expression increased, and mRNA levels of GPX4 and Nrf2 were markedly suppressed (P < 0. 05). Intervention with Yiqi Huoxue Lishui Decoction and/or inhibitors significantly attenuated histopathological damage, reduced AST, ALT, MDA, TNF-α, Fe²⁺ levels, and downregulated TFR1 and Beclin-1 expression (P < 0.05). Concurrently, SOD activity, GPX4 and Nrf2 protein/mRNA expression, and SLC7A11 protein levels were elevated (P <0. 05). No significant difference was observed in the LC3 Ⅱ/Ⅰ ratio across groups(P > 0.05).

Conclusion:

Yiqi Huoxue Lishui Decoction may ameliorate hepatic fibrosis by inhibiting ferroptosis through activation of the Nrf2/GPX4 signaling pathway.

Key words

Liver fibrosis (HF) / Yiqi Huoxue Lishui Decoction / Ferroptosis / Nrf2/GPX4 / Autophagy

引用本文

刘晶晶, 周小琦, 王璐, 童丽君, 戴琦. 益气活血利水汤调控Nrf2/GPX4信号通路抑制铁死亡改善肝纤维化大鼠的机制研究. 中医药学报, 2026 , 54 (6) : 18 -24 . DOI: 10.19664/j.cnki.1002-2392.260113

Jingjing LIU, Xiaoqi ZHOU, Lu WANG, Lijun TONG, Qi DAI. Mechanism of Yiqi Huoxue Lishui Decoction Regulating Nrf2/GPX4 Signaling Pathway to Inhibit Ferroptosis and Improve Liver Fibrosis in Rats[J]. Acta Chinese Medicine and Pharmacology, 2026 , 54 (6) : 18 -24 . DOI: 10.19664/j.cnki.1002-2392.260113

基金

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江西省教育厅科学技术研究项目(GJJ2200944)

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2026年第54卷第6期

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文章信息

doi: 10.19664/j.cnki.1002-2392.260113

接收时间：2025-01-07
首发时间：2026-09-17
出版时间：2026-06-20

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收稿日期：2025-01-07
修回日期：2025-10-24

基金

江西省教育厅科学技术研究项目(GJJ2200944)

作者信息

^1.江西中医药大学，江西南昌 330004

^2.广州中医药大学，广东广州 510405

^3.江西中医药大学附属医院，江西南昌 330006

通讯作者:

^* 戴琦（1970-），女，硕士，副教授，主任中医师，从事肝胆脾胃病相关研究。

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https://castjournals.cast.org.cn/joweb/zyyxb/CN/10.19664/j.cnki.1002-2392.260113

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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