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/BAALC axis was validated using dual-luciferase reporter assays. Intracellular iron concentration and ferroptosis were measured following BAALC knockdown. Phenotypic effects on ESCC cell proliferation and migration were assessed through functional assays. Rescue experiments were conducted to determine BAALC dependency in HOTAIR-mediated malignant progression.

RESULTS

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

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/BAALC pathway. These findings provide new mechanistic insights and potential therapeutic targets for ESCC diagnosis and treatment.