BAY11-7082 Targets RNF25 to Reverse TRIP4 Ubiquitination-dependent NF-κB Activation and Apoptosis Resistance in Renal Cell Carcinoma.

ABSTRACT: NF-κB pathway dysregulation, a common driver of therapy resistance in cancer, promotes survival by suppressing apoptosis. While the anti-apoptotic role of NF-κB is recognized, the molecular mechanisms underlying this process remain poorly defined. Here, we identify the E3 ubiquitin ligase RNF25 as a key mediator of NF-κB-dependent apoptosis resistance in renal cell carcinoma cells, enabling evasion of multiple targeted therapies. Mechanistically, RNF25 binds TRIP4 and catalyzes its non-degradative ubiquitination at lysine 135, disrupting TRIP4-p65 interactions. This modification liberates p65 to activate NF-κB signaling, upregulating anti-apoptotic effectors (e.g., cIAP2, Bcl-2). We further demonstrate that the NF-κB inhibitor BAY11-7082 directly interacts with RNF25, reversi

SUBMITTER: Li L 

PROVIDER: S-EPMC12320230 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature