c-Myc confers vulnerability of colorectal cancer to ferroptosis through interacting with Nrf2

Abstract

Abstract C-Myc is one of the most common oncogenes, and it is overexpressed in various cancers. It is involved in regulating cancer progression, immune remodeling, and metabolic reprogramming, among other processes. However, its role in ferroptosis, a recently reported programmed cell death pathway, is not yet clear. In this study, we found that c-Myc is overexpressed in colorectal cancer. Additionally, c-Myc enhances the sensitivity of colorectal cancer cells to ferroptosis. Mechanistically, c-Myc promotes the ubiquitination of Nrf2, leading to the degradation of Nrf2 protein and ultimately reducing its expression. Nrf2 is a key transcription factor involved in oxidative stress response and has been identified as an important molecule for resisting ferroptosis. Finally, we confirmed that sulfasalazine, a known clinical inducer of ferroptosis, significantly reduces cell proliferation induced by c-Myc. In summary, our study confirms the interaction between c-Myc and Nrf2, enhances the sensitivity of colorectal cancer cells to ferroptosis, and proposes sulfasalazine as a potential therapeutic strategy for tumors with high c-Myc expression.