LINC01446/miR-338-3p/APEX1 Axis Promotes Ferroptosis Defense and Progression in Esophageal Squamous Cell Carcinoma

Abstract

Simple Summary Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular mechanisms to develop targeted therapies. Long non-coding RNAs (lncRNAs) play a critical role in cancer progression. However, the majority of lncRNAs involved in ESCC progression remain to be elucidated. This study aimed to investigate the expression and role of LINC01446 in ESCC, particularly its involvement in tumor progression and ferroptosis defense. Based on bioinformatics analysis of the TCGA and GEO datasets, LINC01446 was significantly upregulated in ESCC and correlated with poorer overall survival (OS). Functional assays revealed that LINC01446 knockdown suppressed ESCC cell proliferation, migration, and invasion. In addition, its knockdown induced ferroptosis in ESCC cells, as evidenced by elevated oxidized C11-BODIPY staining, increased malondialdehyde (MDA) levels, and decreased glutathione (GSH) levels. Mechanistically, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) was identified as a downstream target of LINC01446 using RNA sequencing and Western blotting, the expression of which was positively correlated in ESCC tissues. Further experiments suggested that cytoplasmic LINC01446 might act as a competing endogenous RNA (ceRNA) that sponges miR-338-3p, thereby alleviating its repressive effect on APEX1 expression. Dual-luciferase and AGO2-RIP assays supported a regulatory relationship among LINC01446, miR-338-3p, and APEX1, consistent with a ceRNA-mediated mechanism. Moreover, LINC01446 knockdown suppressed tumor growth and reduced APEX1 expression in vivo, accompanied by increased MDA levels, suggesting enhanced lipid peroxidation and a possible increase in ferroptosis. These findings suggest that the LINC01446/miR-338-3p/APEX1 axis may contribute to ESCC progression and ferroptosis defense, warranting further investigation into its potential therapeutic and prognostic value.