Yi Feiyang, Chen Nianzhi, Zhao Maoyuan, Gu Zhili, Yuan Yun, Tang Xuegui, Liu Fang
Clinical Medicine College of Integrated Chinese and Western Medicine, North Sichuan Medical College, Nanchong, China.
Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Mol Med. 2025 Jun 5;31(1):221. doi: 10.1186/s10020-025-01193-7.
Dehydrodiisoeugenol (DEH) is a primary benzofuran-type neolignan isolated from the Chinese herbal medicine nutmeg, which is used in the treatment of gastrointestinal diseases. This study aims to observe the dual therapeutic effects of DEH on DSS-induced ulcerative colitis (UC) and colorectal cancer (CRC), with a focus on exploring the molecular mechanism by which DEH exerts anti-inflammatory effect in inflammatory cells and induces autophagy in CRC cells. An inflammatory cell model was established by LPS/IFNγ-stimulated RAW264.7 macrophages to observe the anti-inflammatory effect of DEH, while colon cancer cell lines were used to observe the anticancer activity of DEH. DSS-induced mice and subcutaneous tumor model in nude mice were also established to observe the bidirectional regulation of DEH. This study demonstrates that low concentrations of DEH exhibit anti-inflammatory effects in vitro. Importantly, DEH achieves significant inhibition of IκBα degradation and phosphorylation levels, as well as subsequent NF-κB nuclear translocation, while also suppressing the phosphorylation of the MAPK family members JNK, ERK, and p38, by reducing elevated NOD2 expression induced by LPS/IFNγ. In addition, oral administration of DEH improves colitis and colonic barrier damage in DSS-induced mice. Interestingly, at a high concentration of DEH significantly activates the NOD2 signaling pathway to promote autophagy and apoptosis in CRC cells, contributing to its anti-CRC effect. These findings suggest that different concentration of DEH shows bidirectional regulation by improve inflammatory responses in UC and simultaneously possess anti-CRC effects by targeting the NOD2. This highlights DEH as a promising candidate for clinical treatment of UC and CRC.
去氢二异丁香酚（DEH）是从中药材肉豆蔻中分离出的一种主要的苯并呋喃型新木脂素，可用于治疗胃肠道疾病。本研究旨在观察DEH对葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎（UC）和结直肠癌（CRC）的双重治疗作用，重点探索DEH在炎性细胞中发挥抗炎作用以及在CRC细胞中诱导自噬的分子机制。通过脂多糖（LPS）/γ干扰素（IFNγ）刺激的RAW264.7巨噬细胞建立炎性细胞模型，以观察DEH的抗炎作用，同时使用结肠癌细胞系观察DEH的抗癌活性。还建立了DSS诱导的小鼠模型和裸鼠皮下肿瘤模型，以观察DEH的双向调节作用。本研究表明，低浓度的DEH在体外具有抗炎作用。重要的是，DEH可显著抑制IκBα的降解和磷酸化水平以及随后的核因子κB（NF-κB）核转位，同时还通过降低LPS/IFNγ诱导的核苷酸结合寡聚化结构域蛋白2（NOD2）表达升高来抑制丝裂原活化蛋白激酶（MAPK）家族成员c-Jun氨基末端激酶（JNK）、细胞外信号调节激酶（ERK）和p38的磷酸化。此外，口服DEH可改善DSS诱导的小鼠的结肠炎和结肠屏障损伤。有趣的是，高浓度的DEH可显著激活NOD2信号通路，促进CRC细胞的自噬和凋亡，从而产生其抗CRC作用。这些发现表明，不同浓度的DEH通过改善UC中的炎症反应显示出双向调节作用，并通过靶向NOD2同时具有抗CRC作用。这突出了DEH作为UC和CRC临床治疗的有前途的候选药物。
