Erianin triggers ferroptosis in colorectal cancer cells by facilitating the ubiquitination and degradation of GPX4

Abstract

Background

Colorectal cancer (CRC) continues to represent a significant global public health challenge. Ferroptosis, a novel form of cell death dependent on iron and involving lipid peroxidation, has emerged as an effective strategy for treating various cancers with great potential for application.

Purpose

This study aimed to investigate the therapeutic potential of erianin, a novel dibenzyl compound isolated from the well-known herbal medicine Dendrobium chrysotoxum Lindl, in the treatment of CRC through induction of ferroptosis.

Methods

Human CRC HCT116 and SW480 cells were employed for in vitro investigations, while an AOM/DSS CRC animal model was established for in vivo experiments.

Results

The results demonstrated that erianin effectively inhibited the growth of CRC cells and suppressed tumorigenesis in the AOM/DSS CRC animal model. Erianin induced ferroptosis in CRC cells as evidenced by a significant increase in intracellular Fe²⁺ levels and lipid peroxides, along with a decrease in glutathione. Additionally, ferroptosis inhibitors reversed the cytotoxicity of erianin against CRC cells as well as its induction of ferroptosis. Notably, novel glutathione peroxidase 4 (GPX4), a core regulatory factor of ferroptosis, was found to be overexpressed in human primary colon adenocarcinoma tissues compared with normal tissues. However, erianin significantly reduced GPX4 expression by facilitating its ubiquitination and degradation. Furthermore, the overexpression of GPX4 mitigated erianin-induced ferroptotic cell death; conversely, the silencing of GPX4 amplified these effects.

Conclusion

Erianin demonstrates the potential to inhibit CRC by inducing ferroptosis through accelerating the ubiquitination and degradation of GPX4, indicating its promise as a therapeutic candidate against CRC.