Targeting SLC7A11 sensitizes colorectal cancer cells to elesclomol-Cu-induced cuproptosis via the GSH-GPX4 axis.

BACKGROUND

A recently identified type of copper-induced cell death that may contribute to tumor development is cuprotosis. However, uncertainty surrounds its molecular regulation mechanism in colorectal cancer (CRC). Clarifying the regulation mechanism of SLC7A11 in CRC cell cuproptosis was the goal of this investigation.

METHODS

To identify the genes associated with cuproptosis, we combined transcriptome data from TCGA-COAD and GSE83889. Functional experiments including cell viability assays, colony formation, Western blotting, glutathione metabolism analysis, lipid peroxidation staining, and ROS measurements, were performed in CRC cells following SLC7A11 knockdown and treatment with the copper ionophore elesclomol-Cu. Rescue experiments were conducted using exogenous glutathione (GSH) and SLC7A11 inhibitors (erastin, SASP) to validate the mechanisms.

RESULTS

Bioinformatics analysis identified SLC7A11 as a cuproptosis-related gene markedly elevated in CRC and linked with a poor prognosis. Knockdown or pharmacological inhibition of SLC7A11 enhanced elesclomol-Cu-induced cell death, increased intracellular Cu2+ accumulation, and aggravated oxidative stress. Mechanistically, SLC7A11 silencing disrupted glutathione and cystine metabolism, suppressed GPX4 activity, and altered the expression of key cuproptosis regulators. Exogenous glutathione partially reversed these effects. Furthermore, inhibition of SLC7A11 using erastin or SASP drugs enhanced goblet apoptosis and further reduced CRC cell viability.

CONCLUSION

SLC7A11 knockdown regulates intracellular redox balance through the GSH-GPX4 axis, thereby promoting cellular cuproptosis. Targeting SLC7A11 can enhance the sensitivity of CRC cells to copper ionophores and may represent a novel therapeutic strategy to enhance cuproptosis of CRC cells.