Long Non-Coding RNA LINC01614 Promotes Aggressive Phenotypes and Ferroptosis Resistance in Papillary Thyroid Cancer Through a Putative miR-4521/IGF2/PI3K-AKT Signaling Axis

Abstract

Background/Objectives: Papillary thyroid cancer (PTC) is the most common endocrine malignancy and is generally associated with favorable clinical outcomes. However, a subset of tumors develops aggressive phenotypes characterized by increased proliferation, migration, therapeutic resistance, and disease progression. Long non-coding RNAs (lncRNAs) have emerged as important regulators of tumor biology, yet the role of Long Intergenic Non-Protein Coding RNA 1614 (LINC01614) in PTC remains poorly understood. This study investigated the functional role of LINC01614 in PTC and its potential involvement in ferroptosis-associated molecular pathways. Methods: RNA sequencing data from a repository of 44 paired PTC and adjacent normal thyroid tissue samples were analyzed to identify differentially expressed lncRNAs. LINC01614 expression was evaluated in thyroid cell lines, and CRISPR interference (CRISPRi) was used to generate stable LINC01614 knockdown K1 cell lines. Cellular proliferation, migration, clonogenicity, intracellular iron accumulation, lipid peroxidation, cytokine secretion, and ferroptosis-associated gene expression were assessed using qRT-PCR, RNA sequencing, Western blotting, cytokine array analysis, iron quantification assays, and BODIPY C11 lipid peroxidation imaging. Results: LINC01614 was significantly overexpressed in PTC tissues and thyroid cancer cell lines. CRISPRi-mediated repression of LINC01614 reduced cellular proliferation, migration, and clonogenic capacity. Mechanistically, LINC01614 knockdown resulted in an 8.8-fold increase in miR-4521 expression and a 23-fold decrease in IGF2 expression, supporting a potential competing endogenous RNA mechanism. Reduced LINC01614 expression was associated with decreased AKT, GPX4, SLC7A11, and SLC3A2 expression, increased IL-6 secretion, a 3.4-fold increase in intracellular ferrous iron accumulation, and a marked increase in lipid peroxidation following erastin treatment, indicating enhanced sensitivity to ferroptosis. Conclusions: These findings identify LINC01614 as a novel regulator of aggressive PTC phenotypes and ferroptosis resistance. The data support a model in which LINC01614 contributes to thyroid cancer progression through modulation of a miR-4521/IGF2/PI3K/AKT signaling axis and downstream anti-ferroptotic pathways. LINC01614 may represent a promising biomarker and potential therapeutic target in papillary thyroid cancer.