Abstract Background: Chemoresistance remains a key barrier to effective colorectal cancer (CRC) treatment. CWH43, a regulator of membrane-associated protein processing, has been implicated in CRC progression, but its relevance to therapy response and ferroptosis-related vulnerability is unclear. Methods: Public CRC datasets were analyzed to examine associations between CWH43 expression, treatment response patterns, and patient outcomes. CRC cell models with altered CWH43 expression were used to assess responses to chemotherapeutic agents and oxidative-stress-related phenotypes. Enrichment analyses were performed to explore biological processes linked to CWH43 dysregulation. Results: High CWH43 expression correlated with reduced sensitivity to standard chemotherapy and poorer outcomes in advanced CRC. In vitro, CWH43 overexpression promoted a resistant phenotype accompanied by changes in oxidative-stress handling and ferroptosis-associated features. Reducing CWH43 expression increased susceptibility to chemotherapeutic challenge. Conclusions: CWH43 may serve as a previously unrecognized contributor to chemoresistance in CRC, potentially through modulation of redox and ferroptosis-related processes. These findings support CWH43 as a candidate biomarker of therapeutic response and a target for future mechanistic investigation. Citation Format: Yu-Jia Chang, Chien-Yu Huang, Po-Li Wei, Cheng-Chin Lee. CWH43 emerges as a novel therapeutic target linked to chemoresistance in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3107.
Chang et al. (Fri,) studied this question.