Loss of UXS1 Selectively Depletes Pyrimidines and Induces Replication Stress in KEAP1-Mutant Lung Cancer.

ABSTRACT: Kelch-like ECH-associated protein 1 (KEAP1) is the third most commonly mutated gene in non-small cell lung cancer and is associated with poor prognosis. In this study, we investigated synthetic lethal interaction genes in KEAP1-mutated cancer cells and identified a dependency on UDP-xylose synthase 1 (UXS1), which converts UDP-glucuronic acid (UDP-GlcA) to UDP-xylose in the proteoglycan synthetic pathway. UDP-glucose dehydrogenase (UGDH), a transcriptional target of NRF2 that converts UDP-glucose to UDP-GlcA, was highly expressed in KEAP1-mutant tumors. Upon UXS1 knockdown, depletion of UDP-xylose occurred in both KEAP1-mutant and wild-type cells, whereas UDP-GlcA accumulated to a greater extent in the KEAP1-mutant setting. The resulting shortage of available UDP and other pyrimidines slow

SUBMITTER: Gebru MT 

PROVIDER: S-EPMC12666321 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature