CDC26 facilitates ferroptosis through SLC7A11 degradation and cell cycle arrest.

The ubiquitin proteasome system serves as one of the key protein degradation pathways for cellular homeostasis, and its E3 ubiquitin ligase regulates cell survival and death by specifically recognizing the degradation of target proteins. Ferroptosis, a regulated cell death driven by membrane lipid peroxidation, is modulated by the ubiquitin-proteasome system through E3 ubiquitin ligases targeting specific proteins. Based on the screening of 571 UPS-related genes in previous studies, we further selected a subset of 286 E3 ligases for analysis. Subsequently, cell division cycle 26 (CDC26) was identified as an inducer of ferroptosis in in human pancreatic ductal adenocarcinoma (PDAC) cells. CDC26 expression is downregulated during ferroptosis in PDAC. Functionally, CDC26 overexpression enhances ferroptosis by increasing reactive oxygen species (ROS) and lipid peroxidation, while suppressing cell proliferation and invasion. Mechanistically, CDC26 promotes the ubiquitin-mediated degradation of solute carrier family 7 member 11 (SLC7A11), a key ferroptosis inhibitor, and indirectly inhibits the cell cycle, further sensitizing cells to ferroptosis. These findings establish CDC26 as a ferroptosis mediator, highlighting its role in the ubiquitin-proteasome-ferroptosis network and its potential as a therapeutic target for pancreatic cancer.