Computational Metabolomics Reveals the Potential Mechanism of Matrine Mediated Metabolic Network Against Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a complex issue in cancer treatment in the world at present. Matrine is the main active ingredient isolated from Sophora flavescens air and possesses excellent antitumor effects in HCC. However, the specific underlying mechanisms, especially the possible relationships between the anti-HCC effect of matrine and the related metabolic network of HCC, are not yet clear and need further clarification. In this study, an integrative metabolomic-based bioinformatics algorithm was designed to explore the underlying mechanism of matrine on HCC by regulating the metabolic network. Cell clone formation, invasion, and adhesion assay were utilized in HCC cells to evaluate the anti-HCC effect of matrine. A cell metabolomics approach based on LC-MS was used to obtain the differential metabolites and metabolic pathways regulated by matrine. The maximum activity contribution score model was developed and applied to calculate high contribution target genes of matrine, which could regulate a metabolic network based on the coexpression matrix of matrine-regulated metabolic genes and targets. Matrine significantly repressed the clone formation and invasion, enhanced cell–cell adhesion, and hampered cell matrix adhesion in SMMC-7721 cells. Metabolomics results suggested that matrine markedly regulated the abnormal metabolic network of HCC by regulating the level of choline, creatine, valine, spermidine, 4-oxoproline, D-(+)-maltose, L-(−)-methionine, L-phenylalanine, L-pyroglutamic acid, and pyridoxine, which are involved in D-glutamine and D-glutamate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, etc. Our proposed metabolomic-based bioinformatics algorithm showed that the regulating metabolic networks of matrine exhibit anti-HCC effects through acting on MMP7, ABCC1, PTGS1, etc. At last, MMP7 and its related target β-catenin were validated. Together, the metabolomic-based bioinformatics algorithm reveals the effects of the regulating metabolic networks of matrine in treating HCC relying on the unique characteristics of the multitargets and multipathways of traditional Chinese medicine.

Quantitative Proteomics Reveal the Role of Matrine in Regulating Lipid Metabolism

“…Based on these findings, we hypothesize that matrine not only alters LDLR expression levels through transcriptional regulation but also modulates lipid metabolism by affecting metabolic pathway proteins. In addition, since matrine primarily influences lipid metabolism and other metabolic pathways, metabolomics research will undoubtedly enhance our understanding of matrine’s metabolic regulation in future studies, , which will provide a more comprehensive insight into the molecular pathways modulated by matrine.…”

Research Advancements in Pharmacological Activities and Mechanisms of Matrine

“…Creatine is among the power sources utilized by tumor cells during growth (Kazak & Cohen, 2020), and choline can enhance fatty acid usage to avoid the aberrant accumulation of liver fat. Furthermore, matrine can effectively boost intracellular choline levels and ameliorate lipid metabolism issues in HCC (Wang et al, 2022).…”

Matrine inhibits cell proliferation, invasion, and stem cell formation in hepatocellular carcinoma by regulating the ELAVL1/RBM3‐mediated Wnt/β‐catenin signaling pathway

“…There have been a larger number of studies exhibiting that Matrine has multiple pharmacological properties, containing anti‐tumor, anti‐inflammatory, anti‐viral, and analgesic (Lin et al., 2022). In fact, it has been reported that Matrine might repress HCC progression by regulating different targets or pathways (Lin et al., 2020; Wang et al., 2022). Yet, the specific molecular mechanism of Matrine on anti‐tumor role in HCC is still poorly defined.…”