UGDH promotes 5-fluorouracil resistance in colorectal cancer via the ROS-activated PI3K/AKT-EEF1A2-PRDX1 pathway

5-Fluorouracil (5-FU) chemotherapy resistance is a critical determinant of poor prognosis in patients with colorectal cancer (CRC). One critical mechanism underlying this resistance is the clearance of reactive oxygen species (ROS) generated by 5-FU, which diminishes its cytotoxic efficacy. Here, we identified the differential expression of UDP-glucose dehydrogenase (UGDH) in resistant cells through sequencing, and downstream targets EEF1A2 and PRDX1 were identified via immunoprecipitation-mass spectrometry (IP-MS). Stable knockdown and overexpression cell models were generated using a lentiviral system. The effects of gene manipulation on 5-FU resistance in CRC were evaluated both in vitro and in vivo through flow cytometry for reactive oxygen species (ROS) and apoptosis, as well as TUNEL immunofluorescence assays. Sequencing was utilized to enrich the relevant pathways. Our study firstly demonstrates that ROS-induced activation of the PI3K/AKT signaling pathway upregulates UGDH expression. UGDH promotes 5-FU resistance by collaborating with downstream effectors EEF1A2 and PRDX1 to clear ROS and inhibit tumor cell apoptosis. UGDH serves as a potential biomarker for 5-FU resistance in CRC, with its expression levels providing a crucial basis for therapeutic decision-making.