Li Lei, Wang Zixi, Ma Bohan, Ye Qi, Lei Yuzeshi, Lu Mingming, Ye Leihong, Kang Jialu, Huang Wenyue, Xu Shan, Wang Ke, Chen Yule, Liu Jing, Gao Yang, Wang Chenji, Ma Jian, Li Lei
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China.
Int J Biol Sci. 2025 Jul 4;21(10):4410-4427. doi: 10.7150/ijbs.115032. eCollection 2025.
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., , ). 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.
NF-κB信号通路失调是癌症治疗耐药性的常见驱动因素，通过抑制细胞凋亡来促进细胞存活。虽然NF-κB的抗凋亡作用已得到认可，但其潜在的分子机制仍不清楚。在此，我们确定E3泛素连接酶RNF25是肾癌细胞中NF-κB依赖性凋亡抗性的关键介质，可逃避多种靶向治疗。从机制上讲，RNF25与TRIP4结合并催化其在赖氨酸135处的非降解性泛素化，破坏TRIP4-p65相互作用。这种修饰释放p65以激活NF-κB信号，上调抗凋亡效应因子（例如……）。我们进一步证明，NF-κB抑制剂BAY11-7082直接与RNF25相互作用，逆转其促生存作用并恢复凋亡敏感性。我们的研究结果将RNF25确立为通过NF-κB通路调节产生治疗耐药性的可药物化调控因子，并提出以BAY11-7082对RNF25进行药理学靶向作为克服肾恶性肿瘤凋亡抗性的策略。
