A ferroptosis-related competing endogenous RNA network: HOX transcript antisense intergenic RNA/miR-129-5p/brain and acute leukemia, cytoplasmic axis contributes to the malignant progression of esophageal squamous cell carcinoma.

[BACKGROUND] Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related mortality globally, characterized by high incidence, poor prognosis, and limited therapeutic options. While long non-coding RNAs (lncRNAs) and microRNAs have been implicated in ESCC pathogenesis through competing endogenous RNA (ceRNA) networks, the regulatory mechanisms underlying ferroptosis-related ceRNA interactions remain poorly defined. This study aimed to elucidate the functional role and molecular mechanism of the HOX transcript antisense intergenic RNA (HOTAIR)/miR-129-5p/brain and acute leukemia, cytoplasmic (BAALC) axis in ESCC progression.

[METHODS] The regulatory relationship within the HOTAIR/miR-129-5p/ axis was validated using dual-luciferase reporter assays. Intracellular iron concentration and ferroptosis were measured following knockdown. Phenotypic effects on ESCC cell proliferation and migration were assessed through functional assays. Rescue experiments were conducted to determine dependency in HOTAIR-mediated malignant progression.

[RESULTS] Inhibition of expression significantly increased intracellular iron levels and promoted ferroptosis. The HOTAIR/miR-129-5p/ axis markedly enhanced ESCC cell proliferation and migration. Mechanistically, HOTAIR functioned as a ceRNA by sequestering miR-129-5p, thereby alleviating its repression of and upregulating expression. Rescue experiments further demonstrated that the oncogenic effects of HOTAIR were partially mediated through .

[CONCLUSIONS] This study unveils a novel ferroptosis-associated ceRNA regulatory axis in ESCC, demonstrating that HOTAIR promotes malignant progression by modulating the miR-129-5p/ pathway. These findings provide new mechanistic insights and potential therapeutic targets for ESCC diagnosis and treatment.