Wang Chen, Shi Chen-Hao, Bai Hao-Yang, Lu Jun, Hu Hong-Tao, Sun Yu-Mei, Gao Hang, An Hai, Lu Jia-Hui, Zhao Hua-Jun, Zhu Zhi-Hui
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
J Ethnopharmacol. 2025 May 28;348:119912. doi: 10.1016/j.jep.2025.119912. Epub 2025 Apr 30.
The Astragali Radix - Curcumae Rhizoma herb pair (ACHP) originated from the famous traditional Chinese medicine text "YiXueZhongZhongCanXiLu", in which the two herbs were paired to form Chinese herbal compounds commonly used clinically for digestive system tumors, such as hepatocellular carcinoma (HCC). Although ACHP has been inherited for thousands of years in China, its mechanism against HCC remains unclear.
The study aims to evaluate the effect and explore the mechanism of ACHP against HCC.
The efficacy and safety of ACHP against HCC in vivo were evaluated by tumor volume, organ index, H&E staining, hepatic and renal factors. The serum metabolites of ACHP were identified by UPLC-Q-TOF-MS/MS. The key targets and potential mechanisms of ACHP against HCC were screened by transcriptomics, network pharmacology and molecular docking. The effect and induction of ferroptosis of ACHP-containing serum on HCC in vitro was evaluated by MTT, colony formation assay and specific detection kits. The expression of ferroptosis-related proteins and pathways in vivo was detected by immunohistochemistry.
ACHP significantly inhibited tumor proliferation compared to the two herbs used separately, and showed a favorable safety profile. A total of 75 serum metabolites were identified in both positive and negative ion modes. Transcriptomics results revealed that ferroptosis played a key role in the anti-HCC process of ACHP. Network pharmacology and molecular docking results suggested that the anti-HCC effect of ACHP may be related to EGFR/AKT/mTOR pathway and HIF-1α/HO-1/GPX4 axis. In vitro and in vivo experiments further demonstrated that ACHP suppressed oncogenic signaling via the EGFR/AKT/mTOR pathway while inducing lipid peroxidation-related ferroptosis through HIF-1α/HO-1/GPX4 axis, thereby inhibiting HepG2 cells proliferation and HCC mice tumor growth.
ACHP exerts its effects by suppressing oncogenic signaling through the EGFR/AKT/mTOR pathway and inducing lipid peroxidation-related ferroptosis in HCC via the HIF-1α/HO-1/GPX4 axis. This systematic investigation establishes a coherent pharmacological chain from compound identification to mechanism verification, highlighting ACHP's therapeutic potential as a ferroptosis inducer targeting oncogenic signaling networks in HCC.
黄芪 - 莪术药对（ACHP）源自著名的中医典籍《医学衷中参西录》，其中这两味药配伍形成了临床上常用于消化系统肿瘤（如肝细胞癌（HCC））的中药复方。尽管ACHP在中国已传承数千年，但其抗HCC的机制仍不清楚。
本研究旨在评估ACHP对HCC的作用并探索其机制。
通过肿瘤体积、器官指数、苏木精 - 伊红染色、肝脏和肾脏相关指标评估ACHP在体内抗HCC的疗效和安全性。采用超高效液相色谱 - 四极杆 - 飞行时间串联质谱（UPLC - Q - TOF - MS/MS）鉴定ACHP的血清代谢产物。通过转录组学、网络药理学和分子对接筛选ACHP抗HCC的关键靶点和潜在机制。采用MTT法、集落形成实验和特异性检测试剂盒评估含ACHP血清在体外对HCC铁死亡的影响及诱导作用。通过免疫组织化学检测体内铁死亡相关蛋白和通路的表达。
与单独使用两味药相比，ACHP显著抑制肿瘤增殖，且安全性良好。在正离子和负离子模式下共鉴定出75种血清代谢产物。转录组学结果表明铁死亡在ACHP抗HCC过程中起关键作用。网络药理学和分子对接结果提示，ACHP的抗HCC作用可能与表皮生长因子受体（EGFR）/蛋白激酶B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路以及低氧诱导因子 - 1α（HIF - 1α）/血红素加氧酶 - 1（HO - 1）/谷胱甘肽过氧化物酶4（GPX4）轴有关。体外和体内实验进一步证明，ACHP通过EGFR/AKT/mTOR信号通路抑制致癌信号，同时通过HIF - 1α/HO - 1/GPX4轴诱导脂质过氧化相关的铁死亡，从而抑制HepG2细胞增殖和HCC小鼠肿瘤生长。
ACHP通过EGFR/AKT/mTOR信号通路抑制致癌信号，并通过HIF - 1α/HO - 1/GPX4轴在HCC中诱导脂质过氧化相关的铁死亡发挥作用。这项系统研究建立了从化合物鉴定到机制验证的连贯药理链条，突出了ACHP作为靶向HCC致癌信号网络的铁死亡诱导剂的治疗潜力。
