Abstract
Ferroptosis is a distinct form of programmed cell death that differs from other pathways. It is characterized by iron-dependent lipid peroxidation and results in morphologically lethal cellular damage. With advancing insight, triggering ferroptosis is a promising strategy for cancer therapy. RNA-binding proteins (RBPs) comprise a diverse group of molecules that regulate various RNA processes through interactions with transcripts. Research has highlighted the pivotal role of RBPs in controlling biological functions. Evidence indicates that RBPs play important roles in regulating ferroptosis. Heterogeneous nuclear ribonucleoprotein U (HnRNPU) is a well-known RBP involved in RNA splicing, messenger RNA stability and chromatin organization. Elevated HnRNPU expression has been implicated in cancer progression and is associated with poor prognosis. However, the function and underlying mechanisms of HnRNPU in colon adenocarcinoma (COAD) remain poorly understood. Here we identify increased HnRNPU expression in patients with COAD, with higher levels correlating with poor patient survival. HnRNPU knockdown inhibited cell proliferation and induced cell cycle arrest by suppressing cyclin E1 and CDK2. RNA-sequencing analysis revealed HnRNPU's involvement in ferroptosis regulation. In line with this, HnRNPU deletion induced ferroptosis and increased sensitivity to RSL3 treatment and cysteine deprivation. xCT overexpression (SLC3A2/SLC7A11) counteracted the antiproliferative and proferroptotic effects of HnRNPU knockdown. Mechanistically, HnRNPU stabilized the mRNAs of SLC7A11 and SLC3A2 by binding to their 3' untranslated regions, thereby promoting cysteine uptake and glutathione synthesis. Findings demonstrate that HnRNPU promotes proliferation and inhibits ferroptosis by regulating the mRNA stability of SLC7A11 and SLC3A2. Targeting HnRNPU is a potential therapeutic approach for COAD treatment.