Zhao Yong, Shi Guohong, Huang Xiang, Zhang Zhongyuan, Liao Kaijun, Xiong Hao, Feng Zhiqiang, Mao Shihui, Zhang Xu
Department of Urology, Nanping First Hospital Affiliated to Fujian Medical University, No. 317 Zhongshan Road, Yanping District, Nanping City, Fujian Province 353000, China.
Department of Pathology, Nanping First Hospital of Fujian Medical University, No. 317 Zhongshan Road, Yanping District, Nanping City, Fujian Province 353000, China.
Hum Mol Genet. 2025 May 6;34(10):843-851. doi: 10.1093/hmg/ddaf024.
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).
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.
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.
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.
晚期膀胱癌（bc）患者常因复发和耐药等问题预后较差。铁死亡的发现为膀胱癌治疗开辟了新途径；然而，具体的调控机制仍有待探索。本研究旨在探讨影响膀胱癌细胞铁死亡的机制，特别关注低密度脂蛋白受体相关蛋白8（LRP8）的作用。
我们利用逆转录定量聚合酶链反应和蛋白质免疫印迹法评估膀胱癌细胞中LRP8的表达、Wnt/β-连环蛋白信号通路的激活以及脂肪酸合成相关基因的表达。通过评估线粒体膜电位、Fe2+、丙二醛和活性氧水平来测量铁死亡水平的变化。采用异种移植小鼠模型验证LRP8对膀胱癌进展的影响。
细胞实验表明膀胱癌细胞中LRP8表达显著上调。敲低LRP8可诱导膀胱癌细胞发生铁死亡，这一过程是由Wnt/β-连环蛋白信号通路的抑制直接触发的。由LRP8介导的Wnt/β-连环蛋白信号通路的激活上调了硬脂酰辅酶A去饱和酶1（SCD1）的表达，随后导致铁死亡受到抑制。体内实验表明，敲低LRP8显著抑制了膀胱癌的生长，并伴有Wnt/β-连环蛋白-SCD1轴的抑制。
LRP8通过Wnt/β-连环蛋白-SCD1正反馈环介导单不饱和脂肪酸的合成，从而抑制膀胱癌细胞中的铁死亡。这些发现为调控膀胱癌细胞中的铁死亡提供了一个有前景的靶点。
