痉挛解肽表达的化生（SPEM）是胃癌前病变。左金胶囊（ZJC），由中药草乌（Ranunculaceae，中药典名广藿香）和盐肤木（Rutaceae，中药典名石苏）组成，长期以来被用于治疗多种胃肠道疾病。然而，ZJC对SPEM的作用和机制仍不清楚。为阐明ZJC在改善SPEM中的作用并研究其机制，本研究采用250 mg/kg体重的他莫昔芬（TAM）诱导SPEM小鼠，评估ZJC的效果并探究其可能的机制。采用转录组学与网络药理学相结合的策略，探索ZJC在改善SPEM中的靶点和机制。构建了“成分-靶点-通路”网络，并通过RT-qPCR和Western blot实验验证可能的连接。结果显示，ZJC显著减轻了TAM诱导的SPEM小鼠的异常血清指标、胃粘膜结构破坏、胃窝增生、胃粘液增加、CD44和TFF2的大量分泌、胃腺萎缩以及干/祖细胞的大量增殖。通过转录组学和网络药理学分析，得到了与改善SPEM相关的ZJC的50个核心靶标。KEGG结果显示，这些核心靶标在细胞周期和PI3K-AKT信号通路中显著富集。根据蛋白相互作用网络分析，CDK1、CCNB1和CCNA2是排名靠前的靶标，也与细胞周期相关。综合实验表明，ZJC可以通过调节细胞周期相关蛋白（如CDK1、CCNB1、CCNA2）和PI3K-AKT信号通路的异常激活，诱导G2/M期细胞周期阻滞，抑制TAM诱导的恶性增殖。因此，ZJC可能通过抑制细胞周期相关蛋白（CDK1、CCNB1、CCNA2）和PI3K-AKT信号通路的异常激活来改善TAM诱导的SPEM。这一发现支持了将ZJC作为治疗胃癌前病变的潜在药物的使用。版权所有©2023. Elsevier B.V.出版。

Spasmolytic polypeptide-expressing metaplasia (SPEM) is a gastric precancerous lesion (GPL). Zuojin capsule (ZJC), consisting of Coptis chinensis Franch. (Ranunculaceae, recorded in the Chinese Pharmacopoeia as Rhizoma Coptidis) and Tetradium ruticarpum (A.Juss.) T.G.Hartley (Rutaceae, recorded in the Chinese Pharmacopoeia as Fructus Evodiae), has long been used for various gastrointestinal diseases. However, the effect and mechanism of ZJC on SPEM remain unclear.To clarify the role of ZJC in improving SPEM and study its mechanism.The study utilized SPEM mice induced by 250 mg/kg body weight of tamoxifen (TAM) to assess the effects of ZJC and investigate its possible mechanisms. A strategy of transcriptomics combined with network pharmacology was conducted to explore the targets and mechanisms of ZJC in improving SPEM. The "ingredients-target-pathway" network was constructed, and the possible connections were verified by RT-qPCR and Western blot assays.ZJC significantly attenuated the abnormal serological indices, destruction of the gastric mucosal structure, hyperplasia of gastric pits, increased gastric mucus, massive secretion of CD44 and TFF2, oxyntic atrophy and massive proliferation of stem/progenitor cells in TAM-induced SPEM mice. Combined transcriptomics and network pharmacology analysis, 50 core targets of ZJC related to SPEM improvement were obtained. KEGG results showed that the core targets were significantly enriched in the cell cycle, and PI3K-AKT signaling pathway. The top-ranked targets according to PPI network analysis were CDK1, CCNB1, and CCNA2, which are also associated with cell cycle. Combined experiments demonstrated that ZJC can induce G2/M phase cycle arrest and inhibit TAM-induced malignant proliferation by regulating abnormal activation of cell cycle-related proteins such as CDK1, CCNB1, CCNA2 and PI3K-AKT signaling pathways.ZJC may improve TAM-induced SPEM by inhibiting abnormal activation of cell cycle-related proteins (CDK1, CCNB1, CCNA2) and PI3K-AKT signaling pathway. This finding supports the use of ZJC, a famous traditional Chinese medicine compound, as a potential treatment for gastric precancerous lesions.Copyright © 2023. Published by Elsevier B.V.