Abstract / Summary
Ferroptosis is an iron-dependent form of regulated cell death that has emerged as a potential vulnerability in cancer cells under therapeutic stress. However, the mechanisms by which colorectal cancer cells modulate ferroptosis susceptibility remain incompletely understood. In this study, we investigated the role of CWH43, a glycosylphosphatidylinositol-anchor biogenesis-related protein whose role in chemotherapy response has been unclear, in regulating redox balance and ferroptosis-associated vulnerability in colorectal cancer. Integrative analyses of clinical datasets, transcriptomic profiling, and functional experiments were performed using gain- and loss-of-function approaches in CRC cell models. We found that elevated CWH43 expression was associated with adverse clinical outcomes and reduced responsiveness to chemotherapy. Functionally, CWH43 attenuated ferroptosis-associated vulnerability by reducing intracellular reactive oxygen species and lipid peroxidation. Mechanistically, CWH43 promoted redox-adaptive programs involving activation of NRF2-dependent antioxidant signaling, upregulation of the cystine transporter SLC7A11, increased intracellular glutathione availability, and suppression of lipid peroxidation. Genetic or pharmacological disruption of SLC7A11 restored ferroptosis susceptibility and sensitized CWH43-overexpressing colorectal cancer cells to therapeutic stress, whereas ferrostatin-1 partially restored cell viability following erastin-containing treatments. Collectively, these findings identify CWH43 as a regulator of redox adaptation that modulates ferroptosis-associated vulnerability in colorectal cancer, providing insights into stress-adaptive survival mechanisms and chemotherapy resistance in cancer cells.