Abstract
BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Ubiquitination modification is extensively involved in various biological processes, including aerobic glycolysis and tumor development. TP53 mutations are present in nearly half of CRC patients, while in p53-wild type CRC, effective therapeutic targets remain relatively limited. METHODS: We employed bioinformatics methods to systematically analyze the expression and prognostic value of E3 ubiquitin ligase FBXO family members in CRC, with a focus on FBXO39. Through in vitro experiments such as CCK-8 assay, EdU cell proliferation assay, colony formation assay, glucose metabolite measurement, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) analyses, as well as in vivo experiments including cell-derived xenograft models, we elucidated the biological functions of FBXO39 in CRC. Furthermore, we explored its molecular mechanisms through molecular docking, co-immunoprecipitation (Co-IP), and ubiquitination assays. RESULTS: FBXO39 expression was significantly higher in CRC tissues than in adjacent normal tissues, and its high expression was associated with poor patient prognosis. Functional experiments demonstrated that FBXO39 significantly promoted CRC cell proliferation both in vitro and in vivo. Mechanistically, FBXO39 directly bound to the p53 protein and promoted its ubiquitination-mediated degradation in p53-wild type CRC cells. Further investigations revealed that FBXO39 overexpression enhanced the aerobic glycolysis capacity of CRC cells, while its knockdown inhibited this process. Mechanistically, FBXO39 enhanced aerobic glycolysis and promoted tumor cell proliferation by upregulating lactate dehydrogenase A (LDHA) expression in a p53-dependent manner. CONCLUSION: This study reveals a novel mechanism for p53 protein downregulation in p53-wild type CRC, elucidates the role of FBXO39 in regulating aerobic glycolysis through the p53/LDHA axis to promote tumor progression, and provides new insights into the function of FBXO39 in metabolic reprogramming in CRC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-08056-7.