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, reversing its pro-survival effects and restoring apoptosis sensitivity. Our findings establish RNF25 as a druggable orchestrator of therapy resistance through NF-κB pathway modulation and propose pharmacological targeting of RNF25 by BAY11-7082 as a strategy to overcome apoptosis resistance in renal malignancies.