Cdk1-phosphorylated Nur77 accumulates at the centrosome during mitosis to regulate the Cep192-PLK1 signaling axis.

The orphan nuclear receptor Nur77 is a multifunctional regulator involved in diverse cellular processes, including proliferation, survival, and apoptosis, through both transcription-dependent and -independent mechanisms. This regulatory complexity underscores the need for mechanistic studies in defined biological contexts. Here, we uncover a previously unrecognized non-genomic function of Nur77 at the centrosome that promotes mitotic progression in cancer cells. We show that Nur77 is phosphorylated at threonine 143 by cyclin-dependent kinase 1 (Cdk1), leading to its accumulation at the centrosome, where it binds the scaffold protein Cep192. This interaction is critical for maintaining centrosome integrity in tumor cells and facilitating the recruitment of Polo-like kinase 1 (PLK1), a key driver of centrosome maturation. Notably, Cdk1-mediated phosphorylation of Nur77 is aberrantly elevated in tumors, contributing to malignant proliferation through its mitotic role. Depletion of Nur77 or treatment with NMA39, a novel small-molecule Nur77 modulator that disrupts the Nur77-Cep192 interaction, results in mitotic arrest and cell death in tumor cells. These findings reveal a tumor-selective mitotic function of Nur77 and establish a mechanistic rationale for targeting phospho-Nur77 signaling as a cancer vulnerability.