LRRC45 accelerates bladder cancer development and ferroptosis inhibition via stabilizing NRF2 by competitively KEAP1 interaction

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.

Bladder cancer; Ferroptosis; KEAP1/NRF2; LRRC45; Ubiquitination.