LTBP2 Knockdown Promotes Ferroptosis in Gastric Cancer Cells through p62-Keap1-Nrf2 Pathway.

Gastric cancer (GC) is one of the most common gastrointestinal malignancies. Ferroptosis is a new type of peroxidation-driven and iron-dependent cell death. However, the biological functions and exact regulatory mechanisms of ferroptosis in GC remain elusive. Here, we performed RNAi and gene transfection, cell viability assay, lipid peroxidation assay, reactive oxygen species (ROS) assay, glutathione assay, qRT-PCR, Western blotting, and transmission electron microscopy (TEM) to study ferroptosis in gastric cancer. The results revealed that silencing latent transforming growth factor binding proteins (LTBP2) can significantly inhibit GC cell proliferation and decrease cellular GSH levels, reduce GPX4 activity, and increase ROS generation and malondialdehyde (MDA) levels, leading to ferroptosis in GC cells. In addition, we demonstrate that suppression of LTBP2 could regulate the p62-Keap1-Nrf2 pathway, thereby downregulating the GPX4 and xCT expression and upregulating the PTGS2 and 4HNE expression. Our findings described a new role of LTBP2 in regulating ferroptosis, which heralds the prospect of ferroptosis-mediated cancer therapy.