Liu Shenglan, Wu Junhong, Huang Hao, Hu Bin, Xie Dong, Cao Fuqiang, Li Jingxuan, Guo Caiyao, Peng WeiJie, Jin Yanli, Dai Wei
Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, Gannan Medical University, Ganzhou, 341000, China.
Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, China.
Chin Med. 2025 Jul 11;20(1):110. doi: 10.1186/s13020-025-01171-5.
Colorectal cancer (CRC) is a prevalent malignant tumor globally, ranking third in incidence and second in mortality. Metastasis is the main cause of death in patients with CRC. Solanum nigrum L. (SNL), a traditional Chinese medicinal herb endowed with detoxification, blood circulation enhancement, and anti-swelling properties, has been widely used in folk prescriptions for cancer treatment in China. Solamargine (SM) is the major steroidal alkaloid glycoside purified from SNL. However, its role and mechanism against metastatic CRC are not yet clear. The purpose of this study was to evaluate the inhibitory effect of SM on human hepatic metastatic CRC and investigate its underlying mechanism.
CCK-8 assay, colony-formation assay, transwell assay, flow cytometry, tumoursphere formation assay, reverse-transcription quantitative PCR (RT-qPCR), Western blotting, transcriptomic sequencing and ferroptosis analysis were performed to reveal the efficacy and the underlying mechanism of SM in CRC cell lines. In vivo, allograft model, patient-derived xenograft (PDX) model, and liver metastatic model were performed to verify the effect of SM on the growth and metastasis of CRC.
SM was found to suppress hepatic metastasis in CRC by effectively targeting key cellular processes, including proliferation, survival, and stemness. RNA sequencing showed that SM could induce ferroptosis, which was confirmed by elevated lipid reactive oxygen species (ROS) and downregulated glutathione peroxidase 4 (GPX4) and glutathione synthetase (GSS) in CRC cells and xenografts. Induction of ferroptosis by SM was regulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, downregulation of β-catenin was found to be fundamental for the SM-enabled cancer stem cells (CSCs) elimination and metastasis blockage in CRC.
Our results indicated that SM is a promising therapeutic drug to inhibit hepatic metastasis in CRC by inducing ferroptosis and impeding CSCs.
结直肠癌（CRC）是全球一种常见的恶性肿瘤，发病率位居第三，死亡率位居第二。转移是CRC患者死亡的主要原因。龙葵（SNL）是一种具有解毒、活血和消肿特性的传统中草药，在中国民间癌症治疗处方中已被广泛使用。茄解碱（SM）是从SNL中纯化得到的主要甾体生物碱糖苷。然而，其对转移性CRC的作用及机制尚不清楚。本研究的目的是评估SM对人肝转移性CRC的抑制作用，并探讨其潜在机制。
采用CCK-8法、集落形成试验、Transwell试验、流式细胞术、肿瘤球形成试验、逆转录定量PCR（RT-qPCR）、蛋白质印迹法、转录组测序和铁死亡分析，以揭示SM在CRC细胞系中的疗效及潜在机制。在体内，进行同种异体移植模型、患者来源的异种移植（PDX）模型和肝转移模型，以验证SM对CRC生长和转移的影响。
发现SM通过有效靶向关键细胞过程，包括增殖、存活和干性，来抑制CRC的肝转移。RNA测序表明，SM可诱导铁死亡，CRC细胞和异种移植中脂质活性氧（ROS）升高、谷胱甘肽过氧化物酶4（GPX4）和谷胱甘肽合成酶（GSS）下调证实了这一点。SM诱导的铁死亡由核因子红细胞2相关因子2（Nrf2）调节。此外，发现β-连环蛋白的下调是SM实现CRC中癌症干细胞（CSCs）消除和转移阻断的基础。
我们的结果表明，SM是一种有前景的治疗药物，可通过诱导铁死亡和阻碍CSCs来抑制CRC的肝转移。
