结肠直肠癌（CRC）是全球第三大常见的癌症相关致残原因，每年约有185万新病例和85万死亡病例。然而，目前CRC的治疗方案存在许多缺点，包括毒性和非靶向副作用。STAT3（信号转导与转录激活因子3）被认为是CRC治疗的一种有希望的分子靶点。寄生草中富含的一种倍半萜内酯复合物——百足草酯A在鼻咽癌、前列腺癌和乳腺癌细胞中通过抑制STAT3信号传导具有强效的抗癌作用。然而，百足草酯A对CRC的抗癌作用及其作用机制尚未完全阐明。本研究旨在研究STAT3信号在百足草酯A的抗CRC作用中的参与。我们使用HCT-116和CT26细胞模型研究了百足草酯A在体外的抗CRC作用。使用过表达STAT3的HCT-116细胞评估了STAT3信号在百足草酯A的抗CRC作用中的参与。使用人类磷酸化受体酪氨酸激酶阵列对百足草酯A处理后的HCT-116细胞中的49种磷酸化酪氨酸激酶进行筛选。结果表明，百足草酯A抑制了细胞增殖和细胞存活，诱导了细胞凋亡，减少了细胞迁移和侵袭，抑制了血管生成，降低了磷酸化Src（Tyr416），磷酸化JAK2（Y1007/1008）和磷酸化STAT3（Tyr705）的蛋白表达水平，并抑制了STAT3的激活和核定位。百足草酯A还显著降低了STAT3靶基因如MMP-2、VEGF和Bcl-xL的蛋白表达水平。更重要的是，STAT3的过度激活减弱了百足草酯A对细胞存活的作用。所有这些结果表明，百足草酯A通过抑制STAT3信号传导至少部分地发挥了强效的抗CRC作用。我们的发现为进一步探索和开发百足草酯A作为一种针对STAT3的新型植物疗法药物提供了坚实的药理学基础。© 2023 The Author(s).

Colorectal cancer (CRC) is the third most common cause of cancer-related morbidity worldwide, with an estimated of 1.85 million new cases and 850,000 deaths every year. Nevertheless, the current treatment regimens for CRC have many disadvantages, including toxicities and off-targeted side effects. STAT3 (signal transducer and activator of transcription 3) has been considered as a promising molecular target for CRC therapy. Brevilin A, a sesquiterpene lactone compound rich in Centipedae Herba has potent anticancer effects in nasopharyngeal, prostate and breast cancer cells by inhibiting the STAT3 signaling. However, the anti-CRC effect of brevilin A and the underlying mechanism of action have not been fully elucidated. In this study, we aimed to investigate the involvement of STAT3 signaling in the anti-CRC action of brevilin A. Here, HCT-116 and CT26 cell models were used to investigate the anti-CRC effects of brevilin A in vitro. HCT-116 cells overespressing with STAT3 were used to evaluate the involvement of STAT3 signaling in the anti-CRC effect of brevilin A. Screening of 49 phosphorylated tyrosine kinases in the HCT-116 cells after brevilin A treatment was performed by using the human phospho-receptor tyrosine kinase (phospho-RTK) array. Results showed that brevilin A inhibited cell proliferation and cell viability, induced apoptosis, reduced cell migration and invasion, inhibited angiogenesis, lowered the protein expression levels of phospho-Src (Tyr416), phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), and inhibited STAT3 activation and nuclear localization. Brevilin A also significantly reduced the protein expression levels of STAT3 target genes, such as MMP-2, VEGF and Bcl-xL. More importantly, over-activation of STAT3 diminished brevilin A's effects on cell viability. All these results suggest that brevilin A exerts potent anti-CRC effects, at least in part, by inhibiting STAT3 signaling. Our findings provide a strong pharmacological basis for the future exploration and development of brevilin A as a novel STAT3-targeting phytotherapeutic agent for CRC treatment.© 2023 The Author(s).