Li Jia-Xin, Tan Shi-Yu, Li Li-Qi, Zheng Yu-Hong, Zhao Lin, Zhu Hui-Rong, He Hai-Lang, Zhang Yan-Yu, Li Run-Ze, Bao Tian-Yu, Zhang Yi-Zhong, Yang Xiao-Man, Zhang Hao, Chen Hui-Hui, Wu Bo-Wen, Lin Xin, Lin Xiao-Sheng, Lin Yin Cheng, Sui Xin-Bing, Xie Ying, Zhou Xian-Mei, Yan Pei-Yu
Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Macau, China.
Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Pharmacol. 2025 Jun 17;16:1594213. doi: 10.3389/fphar.2025.1594213. eCollection 2025.
KRAS is a commonly mutated gene that is present in approximately 30% of NSCLC patients. Currently, the identification of effective therapies for KRAS-mutant NSCLC is difficult for reasons of the structural and biochemical characteristics of the KRAS protein. Our previous study has revealed that tricin was a bioactive component having selective effects on KRAS-mutant NSCLC cell lines. Thus, our aim in this project was to explore the mechanism by which tricin inhibited the progression of KRAS-mutant NSCLC much more deeply.
First of all, we detected the acute toxicity of an intraperitoneal injection of tricin in mice according to the improved up-and-down procedure. Next, we integrated network pharmacology, molecular docking with transcriptomics analysis and biological methods to probe the underlying mechanisms of tricin in the treatment of patients with KRAS-mutant NSCLC. Furthermore, we explored the pharmaceutical effects of combination therapy with tricin and an anti-PD-1 inhibitor. Finally, we detected and analyzed the data from clinical samples to prepare for the clinical translation of tricin.
Intraperitoneal injection of tricin resulted in low acute toxicity. , tricin inhibited the migration, proliferation and colony formation of KRAS-mutant NSCLC cells in a dose-dependent manner. Mechanistically, tricin inhibited KRAS-mutant NSCLC cell growth primarily by suppressing the PDGF-BB-induced SRC/MAPK/AP-1/PD-L1 signaling pathway. SRC was identified as a potentially crucial target. , combined treatment with tricin and an anti-PD-1 antibody markedly suppressed the growth of tumors. The combination treatment had nearly no toxicity to the organs of the mice. In terms of immune regulation, tricin increased the numbers of CD8 T lymphocytes and the levels of the functional cytokines TNFα, IFNγ, and Granzyme B. Tricin also increased the numbers of B lymphocytes and disrupted the PD-1/PD-L1 pathway. These results indicated that tricin could compensate for the deficiency of immunotherapy and enhance the antitumor activity of immunotherapy. Moreover, the detection of clinical samples indicated that the rate of SRC positivity was higher in elderly patients with KRAS mutations at the early stage. A positive correlation between the expression of SRC and PD-L1 was observed in tumor tissues.
We believe that tricin is a safe and promising agent for the treatment of patients with KRAS-mutated NSCLC. Our study provides an experimental basis for improving the clinical application of traditional Chinese medicine.
KRAS是一种常见的突变基因，约30%的非小细胞肺癌（NSCLC）患者存在该基因变异。目前，由于KRAS蛋白的结构和生化特性，难以确定针对KRAS突变型NSCLC的有效治疗方法。我们之前的研究表明，小麦黄素是一种对KRAS突变型NSCLC细胞系具有选择性作用的生物活性成分。因此，本项目的目的是更深入地探索小麦黄素抑制KRAS突变型NSCLC进展的机制。
首先，我们根据改良的上下法检测了小鼠腹腔注射小麦黄素的急性毒性。接下来，我们整合网络药理学、分子对接与转录组学分析以及生物学方法，以探究小麦黄素治疗KRAS突变型NSCLC患者的潜在机制。此外，我们探讨了小麦黄素与抗PD-1抑制剂联合治疗的药物效果。最后，我们检测并分析临床样本数据，为小麦黄素的临床转化做准备。
腹腔注射小麦黄素导致的急性毒性较低。小麦黄素以剂量依赖的方式抑制KRAS突变型NSCLC细胞的迁移、增殖和集落形成。机制上，小麦黄素主要通过抑制血小板衍生生长因子BB（PDGF-BB）诱导的SRC/丝裂原活化蛋白激酶（MAPK）/活化蛋白-1（AP-1）/程序性死亡配体1（PD-L1）信号通路来抑制KRAS突变型NSCLC细胞生长。SRC被确定为一个潜在的关键靶点。此外，小麦黄素与抗PD-1抗体联合治疗显著抑制了肿瘤生长。联合治疗对小鼠器官几乎没有毒性。在免疫调节方面，小麦黄素增加了CD8 T淋巴细胞数量以及功能性细胞因子肿瘤坏死因子α（TNFα）、干扰素γ（IFNγ）和颗粒酶B的水平。小麦黄素还增加了B淋巴细胞数量并破坏了PD-1/PD-L1通路。这些结果表明，小麦黄素可以弥补免疫治疗的不足并增强免疫治疗的抗肿瘤活性。此外，临床样本检测表明，老年早期KRAS突变患者中SRC阳性率较高。在肿瘤组织中观察到SRC与PD-L1表达之间呈正相关。
我们认为小麦黄素是治疗KRAS突变型NSCLC患者的一种安全且有前景的药物。我们的研究为改善中药的临床应用提供了实验依据。
