CX-5461 inhibits cell proliferation and induces ferroptosis of colorectal cancer cells by inactivating Nrf2 pathway
- Cell Signal. 2025 Nov:135:111998. doi: 10.1016/j.cellsig.2025.111998.
- 1. Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, China.
- 2. Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, China.
- 3. Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, China; Department of ophthalmology, Affiliated Hospital of Yanbian University, Yanji, China.
- 4. Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, China; Department of ophthalmology, Affiliated Hospital of Yanbian University, Yanji, China. Electronic address: [email protected].
Ferroptosis is a newly identified type of cell death, characterized by iron dependent lipid peroxidation. Triggering Ferroptosis is considered a promising target, and efforts have been made to identify Ferroptosis inducers in Cancer. CX-5461 is a RNA polymerase I inhibitors that has been approved by FDA to treat breast and ovarian Cancer patients with BRCA1/2 mutations. In our previous study, we found that CX-5461 inhibited GSH synthesis and promote lipid peroxidation in colorectal Cancer (CRC) cells, suggesting that CX-5461 could induce Ferroptosis. Therefore, we aim to elucidate the anti-cancer activity of CX-5461 in CRC,and the mechanisms of CX-5461-mediated Ferroptosis. As a result, we found that CX-5461 inhibited the proliferation of CRC cells, determined by CCK-8, EdU and colony formation assay. RNA-seq analysis suggested that differentially expressed genes (DEGs) were related to cell adhesion molecular, focal adhesion, and cell cycle, etc. Consistently, we observed that CX-5461 induced cell cycle arrest, and inhibited migration, invasion and EMT progression in CRC cells. Of note, the GSH, SLC7A11 and GPX4 were decreased in CX-5462 treated CRC cells, meanwhile ROS, MDA, and lipid ROS were increased. Furthermore, CX-5461 down-regulated Nrf2. Nrf2 activator THBQ successfully reversed the effect of CX-5461 on cell proliferation and Ferroptosis. Mechanically, CX-5461 induces ubiquitinization of Nrf2. The decreased Nrf2 subsequently down-regulates SLC7A11 and GPX4. In conclusion, these results demonstrated that CX-5461 induced Ferroptosis through inhibiting SLC7A11/GPX4 axis by promoting ubiquitinization of Nrf2 in CRC cells, suggesting that CX-5461 may be a valuable candidate for anti-cancer agent in CRC.