Fan Linwei, Guo Dingfan, Zhu Chao, Gao Chenqi, Wang Yu, Yin Fang, Liu Mengwei, Zhou Yanyu, Wei Tiancheng, Xiong Xinxin, Yu Kuai, Le Aiping
Department of Transfusion Medicine, Key Laboratory of Jiangxi Province for Transfusion Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
The First Clinical Medical School of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
Free Radic Biol Med. 2025 Jan;226:29-42. doi: 10.1016/j.freeradbiomed.2024.11.001. Epub 2024 Nov 8.
Centrosomal dysregulation is closely linked to the genesis and progression of tumors. A comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data has revealed that leucine-rich repeat-containing protein 45 (LRRC45), a centrosome linker protein crucial for maintaining centrosome cohesion and a member of the leucine-rich repeat-containing proteins (LRRCs) family, is significantly upregulated in bladder cancer. Notably, the elevated expression levels of LRRC45 were strongly correlated with a poor prognosis in patients. Furthermore, the depletion of LRRC45 in bladder cancer cells markedly inhibited tumorigenic proliferation and increased intracellular iron and reactive oxygen species (ROS) levels. It ultimately triggered ferroptosis, an iron-dependent form of programmed cell death characterized by lipid peroxidation. Mechanistic studies revealed that LRRC45 exerts its oncogenic effects through competitive interaction with Kelch-like ECH-associated protein 1 (KEAP1), which inhibits the ubiquitin-proteasome-mediated degradation of nuclear factor erythroid 2-related factor 2 (NRF2). This interaction enhances the nuclear translocation of NRF2 and its subsequent anti-ferroptotic activity. In conclusion, our studies highlight the critical role of LRRC45 in enhancing the stability of NRF2, thereby promoting the tumorigenic potential of bladder cancer. These insights suggest that targeting LRRC45 could serve as a promising molecular target for developing novel therapeutic interventions for bladder cancer.
中心体失调与肿瘤的发生和进展密切相关。对单细胞RNA测序（scRNA-seq）数据的综合分析表明，富含亮氨酸重复序列蛋白45（LRRC45），一种对维持中心体凝聚力至关重要的中心体连接蛋白，也是富含亮氨酸重复序列蛋白（LRRCs）家族的成员，在膀胱癌中显著上调。值得注意的是，LRRC45的高表达水平与患者的不良预后密切相关。此外，膀胱癌细胞中LRRC45的缺失显著抑制了致瘤增殖，并增加了细胞内铁和活性氧（ROS）水平。最终引发了铁死亡，一种以脂质过氧化为特征的铁依赖性程序性细胞死亡形式。机制研究表明，LRRC45通过与 Kelch样ECH相关蛋白1（KEAP1）的竞争性相互作用发挥其致癌作用，KEAP1抑制泛素-蛋白酶体介导的核因子红细胞2相关因子（NRF2）的降解。这种相互作用增强了NRF2的核转位及其随后的抗铁死亡活性。总之，我们的研究突出了LRRC45在增强NRF2稳定性从而促进膀胱癌致瘤潜能方面的关键作用。这些见解表明，靶向LRRC45可能成为开发膀胱癌新型治疗干预措施的有前景的分子靶点。
