ILF3 promotes colorectal cancer cell resistance to ferroptosis by enhancing cysteine uptake and GSH synthesis via stabilizing SLC3A2 mRNA

作者：Shuhao Wang, Lu Zhu, Yubing Wang, Yue Han, Qingkun Wang, Wenqing Yang, Lei Zhao, Yu Zhang, Delong Pei, Wankun Huang, Aihua Jin, Zhenhua Lin, Junjie Piao · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07872-x · 被引用次数：8 · 研究领域：Cancer-related molecular mechanisms research、Ferroptosis and cancer prognosis、RNA modifications and cancer

Ferroptosis, a type of programmed cell death dependent on iron, is characterized by lipid peroxidation of cellular membranes. However, the roles and underlying mechanisms of RNA-binding proteins (RBPs) in modulating ferroptosis in colorectal cancer (CRC) have not been fully explored. In this study, RNA sequencing (RNA-seq) analysis identified ILF3, an RBP, as a crucial regulator of ferroptosis in CRC cells. Our research demonstrated that ILF3 depletion suppressed CRC cell growth and increased sensitivity to ferroptosis. Combined analysis of RNA-seq data and amino acid metabolomics indicated a relationship between ILF3 and glutathione (GSH) synthesis. Further investigation confirmed that ILF3 knockdown reduced GSH synthesis by regulating SLC3A2-mediated cystine uptake. Mechanistically, ILF3 enhances SLC3A2 mRNA stability by interacting with its 3' UTR, leading to increased cystine uptake. Notably, our observations revealed a frequent increase in ILF3 levels in patients with CRC, which was associated with poor prognosis. The elevated ILF3 expression in CRC appears to be partly due to stimulation by tumor necrosis factor alpha (TNF-α) from the tumor inflammatory microenvironment. Additionally, TNF-α was found to decrease sensitivity to ferroptosis by promoting ILF3 expression. Co-immunoprecipitation and liquid chromatography-mass spectrometry assays revealed that the E3 ligase TRIM17 is involved in TNF-α-induced ILF3 upregulation. Specifically, TNF-α inhibited the interaction be...