# Cucurbitacin B Inhibits Hepatocellular Carcinoma by Inducing Ferroptosis and Activating the cGAS-STING Pathway

## TL;DR

Cucurbitacin B fights liver cancer by causing cell death and boosting the immune response through a key signaling pathway.

## Contribution

Cucurbitacin B is shown to inhibit hepatocellular carcinoma via ferroptosis and cGAS-STING pathway activation.

## Key findings

- CuB induces ferroptosis by altering SLC7A11, GPX4, TFR1, and ACSL4 expression.
- CuB activates the cGAS-STING pathway, increasing IFN-β and immune response markers.
- The study reveals a new mechanism for tumor treatment involving ferroptosis and immune signaling.

## Abstract

The incidence of primary liver cancer is increasing annually, with extremely high mortality and suboptimal therapeutic outcomes. The inefficient presentation of tumor antigens and low infiltration of specific cytotoxic T lymphocytes (CTLs) result in insufficient immunogenicity, which limits the efficacy of immunotherapy. Despite the popularity of immune checkpoint inhibitors (ICIs), insufficient immune activation means only a small subset of hepatocellular carcinoma (HCC) patients exhibit clinical responses to ICIs, showing significant inter-individual variability. The activation of the cyclic GMP-AMP synthase(cGAS)- stimulator of interferon genes(STING) pathway initiates the expression of type I interferons (IFNs) and inflammatory cytokines, promoting the formation of a pro-inflammatory environment at the tumor site. This pathway enhances anti-tumor immune responses by facilitating antigen processing and presentation, T cell priming and activation, and remodeling of the immunosuppressive microenvironment. Our research found that cucurbitacin B (CuB), a natural component derived from traditional Chinese medicine, had significant anti-hepatocellular carcinoma properties and exerted anti-tumor effects through the cGAS-STING pathway. Specifically, CuB regulated ferroptosis by down-regulating the expression of Solute Carrier Family 7 Member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) and upregulating the expression of Transferrin Receptor Protein 1 (TFR1) and Long-chain Acyl-CoA Synthetase 4 (ACSL4). These actions involved lipid substrates, iron ion homeostasis, and antioxidant defense systems. The release of mitochondrial DNA (mtDNA) triggered by ferroptosis activated the cGAS-STING immune signaling pathway, leading to the up-regulation of cGAS, phosphorylated STING (p-STING), phosphorylated TANK-binding kinase 1 (TBK1), phosphorylated Interferon regulatory factor3 (IRF3), and Interferon-β (IFN-β). This cascade activation pattern provides new insights into the drug treatment of tumors.