CELF2 is a tumor suppressor that modulates SLC7A11 and promotes ferroptosis in stomach adenocarcinoma.

Stomach adenocarcinoma (STAD) is among the most prevalent malignant gastrointestinal tumors worldwide. Ferroptosis, a relatively new form of programmed cell death, has garnered significant attention for its role in cancer molecular mechanisms and therapeutic strategies. Therefore, it is particularly important to explore the mechanism of key molecules in ferroptosis on STAD. In our study, CUGBP Elav-like family member 1 (CELF2) was identified to be lowly expressed in STAD tumor tissues at both mRNA and protein levels. Next, CELF2 effectively inhibited the growth and migration of STAD cells both in vitro and in vivo. RNA-seq analysis of AGSCELF2 and AGSNC cells showed that the functions of differentially expressed genes were enriched in the glutathione metabolism and ferroptosis pathway. CELF2 increased the levels of key ferroptosis markers, including ROS, MDA, Fe²⁺ and 4-HNE, while reducing GSH levels. Furthermore, CELF2 enhanced the susceptibility of STAD tumor cells to ferroptosis. Interestingly, the expression levels of CELF2 and Solute carrier family 7 member 11 (SLC7A11) were negatively correlated in RNA-seq data and TCGA database. RIP and RNA pull-down assays confirmed the interaction between CELF2 and SLC7A11. Overexpression of SLC7A11 reversed the effects of CELF2 on STAD growth and ferroptosis levels. Moreover, Ferroptosis inhibitor Ferrostatin-1 effectively rescued the inhibitory effect of CELF2 overexpression on proliferation of tumor cells. CELF2 is a tumor suppressor that promotes the level and susceptibility of ferroptosis in STAD cells by targeting SLC7A11. Implications: This study offers valuable molecular insights for the development of ferroptosis-targeted therapies for STAD.