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

Abstract 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.