Abstract Peritoneal dissemination is the major cause of mortality in epithelial ovarian cancer (EOC) and requires tumor cells to survive in a detached state by evading anoikis. However, the molecular mechanisms supporting anchorage-independent survival remain poorly defined. Here, we identify glutamate dehydrogenase 1 (GLUD1) as a key regulator of anoikis resistance and metastatic progression in EOC. GLUD1 expression was elevated in metastatic EOC tissues and associated with unfavorable clinical outcomes. Loss of GLUD1 impaired anoikis resistance and reduced metastatic capacity of ovarian cancer cells in vitro, while markedly suppressing peritoneal dissemination and prolonging survival in vivo. Mechanistically, GLUD1 was found to interact with a key protein ARAF, the A-Raf proto-oncogene. By limiting ubiquitin–proteasome-mediated degradation of ARAF, GLUD1 exerted a non-enzymatic function that stabilized ARAF protein levels and sustained MEK/ERK signaling. Together, these findings reveal a non-canonical role of GLUD1 in regulating protein stability and identify the GLUD1–ARAF axis as a critical mechanism supporting anchorage-independent survival during peritoneal dissemination of EOC.
Feng et al. (Thu,) studied this question.