On August 13, the research team led by Qingqing Wang from Zhejiang University published a research paper titled "Berberine Protects against Hepatocellular Carcinoma Progression by Regulating Intrahepatic T Cell Heterogeneity" in the journal Advanced Science. In this study, the researchers established an orthotopic liver cancer mouse model and treated it with different doses of Berberine. Berberine can effectively reduce the tumor burden of liver cancer mice. Flow cytometry showed changes in the tumor immune landscape after Berberine treatment, revealing the enhancement of T lymphocyte effector function. Among them, Berberine reduced the proportion of TCRbhiPD-1hiCD69+CD27+ effector CD8+ T lymphocytes and increased the proportion of Ly6ChiTCRb+CD69+CD27+CD62L+ central memory CD8+ T lymphocytes. Single-cell RNA sequencing further clarified the effect of Berberine on the transcriptional profile of liver immune cells and confirmed the phenotypic heterogeneity of T lymphocytes in the immune microenvironment of liver cancer. In addition, berberine may regulate antitumor immunity in liver cancer by modulating cytokine-mediated receptor-ligand interactions between immune cells. Taken together, these findings improve the understanding of the role of berberine in preventing HCC and highlight the role of berberine in regulating intrahepatic T cell heterogeneity. Berberine is expected to become a therapeutic strategy to inhibit liver cancer progression.
Liver cancer is the third leading cause of cancer-related death, among which hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. In the past decade, systemic therapies including immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and monoclonal antibodies have changed the traditional treatment paradigm of HCC. It is estimated that single-agent ICIs provide substantial clinical benefits to 15-20% of responders, but face the challenge that biomarkers cannot identify this population. Therefore, it is necessary to explore new therapeutic strategies to improve the treatment prospects of HCC. The liver immune microenvironment plays a crucial role in the development of liver cancer. For example, it has been observed that T cells and B cells infiltrating tumors interact, leading to local immune activation and control of liver cancer progression. A study using single-cell RNA sequencing (scRNA-seq) revealed that exhausted CD8+T cells and infiltrating Treg cells may undergo clonal expansion in the liver cancer microenvironment.
Unlike the typical exhausted state observed in primary liver cancer, CD8+T cells in early recurrent liver cancer exhibit reduced cytotoxicity and clonal expansion similar to innate immunity, which may explain the impaired antitumor immune function and poor prognosis associated with liver cancer. Therefore, regulating the tumor immune microenvironment (TIME) may help develop effective liver cancer treatments.
Berberine is an isoquinoline alkaloid extracted from the roots, barks, and rhizomes of plants such as Coptis chinensis and Phellodendron chinense, with multiple pharmacological effects. Previous studies have shown that Berberine alleviates non-alcoholic fatty liver disease by reducing gluconeogenesis and lipid synthesis. In addition, Berberine has been reported to inhibit liver cancer by activating PPARδ to trigger apoptosis and promote butyrate production by intestinal microorganisms. In recent years, researchers have paid more and more attention to the immunomodulatory properties of Berberine. The researchers found that Berberine inhibits non-small cell lung cancer by reducing PD-L1 expression and enhancing the immune function of tumor-infiltrating T cells. Another study showed that Berberine promoted the transformation of immunosuppressive M2 macrophages into tumor-killing M1 macrophages and restored the anti-tumor cytotoxicity of T cells. However, the exact mechanism by which Berberine regulates the immune response in liver cancer has not yet been discovered.
To investigate the potential of Berberine for the treatment of HCC, the researchers established an orthotopic HCC mouse model. After one week of adaptive feeding, Hepa 1-6 cells were injected into the left lobe of the liver of mice, and then the mice were given intraperitoneal Berberine injections. According to the Berberine dose, the mice were divided into three groups: HC group (control group), LB group (low-dose Berberine, 10 mg/kg), and HB group (high-dose Berberine, 30 mg/kg). Berberine was administered once every two days for a total of 14 days. After the mice were sacrificed, the mouse livers were collected and the tumor tissues were removed for further analysis. The results showed that there was no statistically significant difference in the body weight of the three groups of mice. However, the tumor volume of mice treated with Berberine was significantly reduced. In particular, high-dose Berberine treatment showed a more significant reduction in tumor volume and weight compared with the LB group (p<0.05), indicating that Berberine showed a dose-dependent trend in reducing HCC burden in mice. In summary, Berberine showed efficacy in reducing tumor burden in mouse models, suggesting that it may have the function of preventing HCC progression.
CellChat was used to determine the ligand-receptor interactions and communication networks between various immune cell types. Compared with the HC group, the researchers observed an increase in overall cell-cell interactions after high-dose Berberine treatment. Ligand-receptor analysis revealed that high-dose Berberine regulated the signal transduction of liver immune cells to CD4+T cells mainly through chemokine ligand-receptor pairs (such as CCL3-CCR5, CCL5-CCR5, CXCL16-CXCR6) and SPP1-(ITGA+ITGB) ligand/receptor pairs (such as SPP1-(ITGA4+ITGB1), SPP1-(ITGAV+ITGB1). In addition, Berberine mainly mediated the intercellular communication between CD4+T cells and immune cells such as MoMF and Kupffer cells through ligand/receptor pairs including CCL5-CCR1, CCL5-CCR5, macrophage migration inhibitory factor (MIF)-(CD74+CD44), LGALS9-CD44, LGALS9-CD45, LGALS9-HAVCR2 and SPP1-(ITGA+ITGB). In addition, high-dose Berberine regulates the interaction between liver cancer immune cells and CD8+T cells through ligand-receptor pairs such as CCL3-CCR5, CCL5-CCR5, CXCL6-CXCR6, and SPP1-(ITGA4+ITGB1). Berberine mainly promotes the communication between CD8+T cells and other immune cells through ligand-receptor pairs such as CCL5-CCR1, CCL5-CCR5, and SPP1-(ITGA+ITGB). In addition, high-dose Berberine treatment can also induce specific signals in CD8+T cells, including TGFβ, IL1, and GDF. In summary, the anti-liver cancer effect of high-dose Berberine may be achieved by regulating the ligand-receptor interaction between immune cells mediated by cytokines and chemokines, thereby regulating the liver immune microenvironment.
In conclusion, the results of this study indicate that Berberine prevents the development of HCC by regulating the heterogeneity of intrahepatic T lymphocytes, specifically increasing the proportion of central memory CD8+T cells while reducing the proportion of effector CD8+T cells, thereby reversing T cell exhaustion. In addition, Berberine can also inhibit HCC by regulating the cytokines secreted by T lymphocytes and affecting their differentiation state. This study provides new insights into the immunomodulatory mechanism of Berberine in HCC, indicating its potential application prospects in the management of HCC.
This article was independently created and published by Herbfields.net.