LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop

Background: Advanced bladder Cancer (bc) patients often have poor prognoses due to issues such as recurrence and drug resistance. The discovery of Ferroptosis has opened new avenues for bc treatment; however, the specific regulatory mechanisms remain to be explored. This study aimed to investigate the mechanisms influencing Ferroptosis in bc cells, with a particular focus on the role of low-density lipoprotein receptor-related protein 8 (LRP8).

Methods: We utilized reverse transcription-quantitative polymerase chain reaction and western blot to assess the expression of LRP8 in bc cells, activation of the Wnt/β-catenin signaling pathway, and the expression of genes related to fatty acid synthesis. We measured changes in Ferroptosis levels by evaluating mitochondrial membrane potential, Fe2+, malondialdehyde, and Reactive Oxygen Species levels. A xenograft mouse model was employed to validate the impact of LRP8 on bc progression.

Results: Cell experiments demonstrated a significant upregulation of LRP8 expression in bc cells. Knockdown of LRP8 induced Ferroptosis in bc cells, a process directly triggered by the inhibition of the Wnt/β-catenin signaling pathway. Activation of the Wnt/β-catenin signaling pathway mediated by LRP8 upregulated the expression of stearoyl-CoA desaturase 1 (SCD1), subsequently leading to the suppression of Ferroptosis. In vivo experiments indicated that LRP8 knockdown significantly impaired bc growth, accompanied by inhibition of the Wnt/β-catenin-SCD1 axis.

Conclusion: LRP8 mediates the synthesis of monounsaturated fatty acids through the Wnt/β-catenin-SCD1 positive feedback loop, thereby inhibiting Ferroptosis in bc cells. These findings provide a promising target for the regulation of Ferroptosis in bc cells.