Liu Xiangjun, Li Yu, Yuan Chenyue, Zhao Yong, Zhou Lin, Yan Yuting, Ren Jianlin, Liu Qingzhong
Laboratory Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhijiang Road, Shanghai, 200071, China.
Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhijiang Road, Shanghai, 200071, China.
Phytomedicine. 2025 Jul 25;143:156833. doi: 10.1016/j.phymed.2025.156833. Epub 2025 May 6.
Colorectal cancer (CRC), as one of the most common cancers globally, poses a significant challenge to public health due to its high incidence and mortality rates. This underscores the need for continuous exploration of new therapeutic targets and effective drugs. Sophocarpine (SC), a natural compound derived from traditional Chinese medicine, holds considerable therapeutic potential in the treatment of CRC, however, the relevant mechanisms remains unclear.
This study aims to explore the anti-tumor effects of SC against CRC by modulating gut microbiota, and uncover potential mechanisms linking SC's therapeutic effects to gut microbiota regulation by analyzing the impact of SC on microbiota composition and CRC progression.
This study explores the impact of SC on the gut microbiota in CRC by constructing subcutaneous xenograft tumors of CRC and integrating 16S rRNA sequencing and RNA transcriptomic sequencing. The fecal microbiota transplantation (FMT) mouse model was used to validate the biological function of SC in correcting gut microbiota dysbiosis to treat CRC. Subsequently, we conducted in vitro studies on the molecular mechanisms by which SC regulates the gut microbiota as an effective hallmark of CRC treatment, using lipopolysaccharide (LPS) to simulate an inflammatory gut microbiota environment and P38 MAPK knockdown cell line.
SC significantly inhibited CRC cell proliferation with IC values of 2.547±0.256 μM for HCT116 and 2.851±0.332 μM for LoVo cells. In vivo experiments demonstrated that SC effectively suppressed tumor growth in xenograft models. 16S rRNA sequencing revealed that SC modulated gut microbiota composition, particularly affecting Bacteroides and Alistipes populations. SC significantly reduced the levels of inflammatory factors and inhibited the MAPK signaling pathway, as evidenced by decreased p-JNK, p-p38 MAPK, and p-NF-κB p65 expression.
Current clinical practice still lacks effective therapeutic agents targeting CRC through gut microbiota modulation. This study presents the first evidence that SC, a natural compound, exhibits dual-action therapeutic efficacy against CRC progression by simultaneously modulating gut microbial composition and suppressing MAPK pathway-mediated inflammatory responses. These findings highlight SC's novel therapeutic potential as a promising microbiota-regulating candidate for CRC intervention, offering an innovative approach that bridges microbial ecology with cancer signaling pathways.
结直肠癌（CRC）是全球最常见的癌症之一，因其高发病率和死亡率对公共卫生构成重大挑战。这凸显了持续探索新治疗靶点和有效药物的必要性。槐果碱（SC）是一种源自中药的天然化合物，在CRC治疗中具有相当大的治疗潜力，然而，相关机制仍不清楚。
本研究旨在通过调节肠道微生物群来探索SC对CRC的抗肿瘤作用，并通过分析SC对微生物群组成和CRC进展的影响，揭示将SC的治疗效果与肠道微生物群调节联系起来的潜在机制。
本研究通过构建CRC皮下异种移植瘤并整合16S rRNA测序和RNA转录组测序，探索SC对CRC肠道微生物群的影响。采用粪便微生物群移植（FMT）小鼠模型验证SC纠正肠道微生物群失调以治疗CRC的生物学功能。随后，我们使用脂多糖（LPS）模拟炎症性肠道微生物群环境和P38 MAPK敲低细胞系，对SC调节肠道微生物群作为CRC治疗有效标志的分子机制进行了体外研究。
SC显著抑制CRC细胞增殖，HCT116细胞的IC值为2.547±0.256 μM，LoVo细胞的IC值为2.851±0.332 μM。体内实验表明，SC有效抑制异种移植模型中的肿瘤生长。16S rRNA测序显示，SC调节肠道微生物群组成，尤其影响拟杆菌属和阿利斯杆菌属种群。SC显著降低炎症因子水平并抑制MAPK信号通路，p-JNK、p-p38 MAPK和p-NF-κB p65表达降低证明了这一点。
目前的临床实践仍然缺乏通过调节肠道微生物群靶向CRC的有效治疗药物。本研究首次证明，天然化合物SC通过同时调节肠道微生物组成和抑制MAPK途径介导的炎症反应，对CRC进展具有双重作用的治疗效果。这些发现突出了SC作为一种有前途的调节微生物群的CRC干预候选药物的新治疗潜力，提供了一种将微生物生态学与癌症信号通路联系起来的创新方法。
