This study reveals a novel mechanism of Bevacizumab in liver cancer treatment, demonstrating its dual regulatory roles in inducing ferroptosis and enhancing CD8+ T cell-mediated immunity. These findings provide critical molecular insights for developing combination therapies targeting both tumor cell death pathways and anti-tumor immune responses.
Literature Overview
This article titled 'Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9', published in Acta Pharmacologica Sinica, systematically investigates the novel mechanism of Bevacizumab in liver cancer treatment through ferroptosis induction and CD8+ T cell immune activation via the HAT1-IL-9 signaling axis.
Background Knowledge
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited therapeutic options and strong resistance to conventional chemotherapy and radiotherapy. Recently, anti-angiogenic therapy (e.g., Bevacizumab) combined with immune checkpoint inhibitors has emerged as a first-line treatment strategy for HCC. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has become a promising therapeutic target in oncology. CD8+ T cells play central roles in anti-tumor immunity, with their activity closely associated with cytokine secretion including IL-2 and Granzyme B. However, whether or not and how Bevacizumab regulates HCC progression through ferroptosis and immune modulation remains unclear. This study systematically elucidates the dual mechanisms of Bevacizumab in HCC through RNA sequencing, cellular experiments, and animal models, providing theoretical support for clinical combination therapies.
Research Methods and Experiments
The research team performed RNA sequencing analysis on human hepatoma HepG2 cells following Bevacizumab treatment, identifying key genes associated with ferroptosis and immune regulation (e.g., VEGF, PI3K, HAT1, SLC7A11, IL-9). Subsequently, Western blot, qPCR, GSH/GSSG ratio assays, lipid ROS detection, and iron content measurements were conducted to validate Bevacizumab's effects on ferroptosis. In mouse models, Hep1-6 cell-transplanted animals received Bevacizumab alone or combined with ferroptosis inducers (e.g., erastin), with tumor growth and immune cell activity evaluated. Clinical HCC tissue samples were analyzed to correlate gene expression levels of VEGF, HAT1, IL-9 with patient prognosis.
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes the first evidence of Bevacizumab's dual therapeutic mechanisms in hepatocellular carcinoma: tumor growth suppression through ferroptosis induction and improved anti-tumor immunity via enhanced CD8+ T cell function. These findings provide molecular foundations for combination strategies targeting VEGF with immune checkpoint modulators or ferroptosis inducers. Future investigations should evaluate clinical translational potential of Bevacizumab combinations with ferroptosis inducers or immune enhancers, while exploring HAT1 and IL-9 as predictive biomarkers for therapeutic response.
Conclusion
In summary, this study demonstrates that Bevacizumab exerts novel regulatory mechanisms in hepatocellular carcinoma beyond traditional anti-angiogenic effects. It suppresses tumor growth through VEGF/PI3K/HAT1/SLC7A11-mediated ferroptosis induction, while simultaneously enhancing anti-tumor immunity by downregulating HAT1 to upregulate miR-143 and increase IL-9 expression/secretion, ultimately activating CD8+ T cells. These discoveries provide important theoretical foundations for HCC treatment strategies and identify potential biomarkers (HAT1, IL-9) for predicting therapeutic efficacy and guiding personalized treatment decisions.
