Inflammatory bowel disease (IBD) is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract, which is lack of effective drug targets and medications. To identify novel therapeutic agents against consistent targets, we exploited a systems pharmacology–driven framework that incorporates drug-target networks of natural product and IBD disease genes. Our in silico approach found that Ligustilide (LIG), one of the major active components of Angelica acutiloba and Cnidium Officinale, potently attenuated IBD. The following in vivo and in vitro results demonstrated that LIG prevented experimental mice colitis induced by dextran sulfate sodium (DSS) via suppressing inflammatory cell infiltration, the activity of MPO and iNOS, and the expression and production of IL-1β, IL-6, and TNF-α. Subsequently, the network analysis helped to validate that LIG alleviated colitis by inhibiting NF-κB and MAPK/AP-1 pathway through activating PPARγ, which were further confirmed in RAW 264.7 cells and bone marrow–derived macrophages in vitro. In summary, this study reveals that LIG activated PPARγ to inhibit the activation of NF-κB and AP-1 signaling thus eventually alleviated DSS-induced colitis, which has promising activities and may serve as a candidate for the treatment of IBD.

Graphical abstract

炎症性肠病（IBD）是一种慢性特发性疾病，导致胃肠道炎症，缺乏有效的药物靶点和药物。为了识别针对一致靶点的新型治疗剂，我们利用了一个系统药理学驱动的框架，该框架结合了天然产物和 IBD 疾病基因的药物靶点网络。我们的计算机方法发现，藁本内酯 (LIG) 是当归和蛇床子的主要活性成分之一，有效减毒 IBD。以下体内和体外结果表明，LIG 通过抑制炎症细胞浸润、MPO 和 iNOS 活性以及 IL-1β、IL-6、和 TNF-α。随后，网络分析有助于验证 LIG 通过激活 PPARγ 抑制 NF-κB 和 MAPK/AP-1 通路来缓解结肠炎，这在体外 RAW 264.7 细胞和骨髓来源的巨噬细胞中得到了进一步证实。总之，本研究表明，LIG 激活 PPARγ 以抑制 NF-κB 和 AP-1 信号传导的激活，从而最终缓解 DSS 诱导的结肠炎，具有良好的活性，可作为 IBD 治疗的候选药物。

图形概要