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Targeting the deubiquitinase activity of USP20 resensitizes 5-FU-resistant colorectal cancer cells
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DOI：10.1016/j.gendis.2026.102363.png)
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Abstract
En 中文
Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide, with 5-fluorouracil (5-FU) being one of the most commonly used chemotherapeutic agents. However, the development of resistance to 5-FU presents a significant obstacle in the effective treatment of CRC. In this study, we investigate the role of USP20, a deubiquitinase, in mediating 5-FU resistance in CRC. Our findings show that USP20 is highly expressed in 5-FU-resistant CRC cell lines and clinical samples, and its elevated expression correlates with poor prognosis in CRC patients. Through immunoprecipitation and ubiquitination experiments, we demonstrate that USP20 stabilizes the autophagy receptor SQSTM1 by directly binding to and catalyzing its deubiquitination, which in turn inhibits autophagy-dependent ferroptosis, two key pathways involved in cancer cell death. Inhibition of the USP20–SQSTM1 axis effectively resensitizes 5-FU-resistant CRC cells to chemotherapy by promoting autophagy-dependent ferroptosis, thereby suppressing tumor cell proliferation and migration. In vivo, targeting the USP20–SQSTM1 axis in combination with 5-FU significantly reduces tumor growth, highlighting the potential therapeutic benefits of this approach. Our results suggest that targeting the USP20–SQSTM1 axis could be a promising strategy for overcoming 5-FU resistance in CRC and improving patient outcomes.
Keywords:
Colorectal cancer (CRC)
Ferroptosis
SQSTM1
USP20
5-FU resistance
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