Targeting the SMAD3/CISD2 axis suppresses bladder cancer progression by promoting ferroptosis in mesenchymal-like bladder cancer cells

作者：Yulin Sun, Jianhui Wang, Da Gu, Huanmin Lou, Jinpeng Sun, Zilian Cui, Weiting Kang · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-08339-9 · 被引用次数：4 · 研究领域：Ferroptosis and cancer prognosis、Bladder and Urothelial Cancer Treatments、TGF-β signaling in diseases

The poor prognosis of bladder cancer (BCa) is primarily attributed to the acquisition of invasive and metastatic capabilities by tumor cells through epithelial-mesenchymal transition (EMT), yet the dynamic alterations in ferroptosis during EMT and their regulatory mechanisms remain unelucidated. This study is the first to reveal the mechanism by which the Smad3/CISD2 signaling axis regulates ferroptosis in mesenchymal-like bladder cancer cells. Clinical sample analysis demonstrated significantly reduced expression of E-cadherin and upregulation of N-cadherin and Vimentin in muscle-invasive bladder cancer tissues (MIBC), with EMT-related marker levels correlating with overall survival rates in BCa patients. In TGF-β1-induced mesenchymal-like bladder cancer cells, ferroptosis-related genes (GPX4, SLC7A11) were markedly elevated, alongside increased lipid peroxides (LPO) and glutathione (GSH) levels. However, mesenchymal-like bladder cancer cells exhibited heightened sensitivity to the ferroptosis inducer Erastin, showing more pronounced suppression of proliferation, elevated ROS, higher LPO and MDA levels, and reduced GSH, confirming their enhanced susceptibility to ferroptosis. RNA-seq revealed significant downregulation of Smad3 in ferroptosis inducer treated mesenchymal-like bladder cancer cells. Smad3 knockdown further exacerbated ferroptosis markers (elevated Fe²⁺, ROS, LPO; decreased GSH), inhibited migration, invasion, and proliferation-phenotypes reversible by ferroptos...