Integrated transcriptomic and functional analysis identifies an SLC7A11-associated lncRNA program in papillary thyroid carcinoma

Background Tumor progression is shaped by coordinated transcriptional programs that support metabolic stress adaptation and remodel interactions with the immune microenvironment. SLC7A11 is a major regulator of cellular cystine metabolism and redox homeostasis and is also closely linked to susceptibility to disulfide stress. However, the long non-coding RNA (lncRNA) programs associated with SLC7A11-dependent stress states in papillary thyroid carcinoma remain poorly characterized. Methods Transcriptomic, clinicopathological, and somatic mutation data from The Cancer Genome Atlas thyroid carcinoma cohort (TCGA-THCA), comprising primarily papillary thyroid carcinoma, were integrated to identify lncRNAs associated with an SLC7A11-centered stress-related transcriptional network. Penalized regression was used for feature reduction and generation of a seven-lncRNA score, which was subsequently examined in relation to clinical outcome, tumor-associated pathways, immune programs, and genomic features. Expression of candidate lncRNAs was evaluated in clinical specimens. Functional relevance of selected lncRNAs was further assessed by siRNA-mediated silencing in thyroid cancer cells followed by proliferation, migration, and drug-response assays based on cell viability measurements. Results We identified a seven-lncRNA transcriptional program associated with the SLC7A11-centered network. A higher program score was associated with unfavorable clinical outcome and showed stronger discriminatory value in patients with more advanced disease. Transcriptomic analyses linked the high-score state to immune- and cytokine-related pathways, increased expression of multiple immune checkpoint molecules, and altered estimated immune-cell infiltration, collectively revealing features consistent with an immune-recognizable but potentially functionally constrained tumor phenotype. High-score tumors also displayed distinct somatic mutation patterns and lower tumor mutational burden. Among the seven lncRNAs, AC107071.1, AC073957.3, and PRKAR1B-AS1 were consistently overexpressed in tumor tissues and were selected for functional interrogation. Silencing these lncRNAs reduced proliferation and migration of thyroid cancer cells and enhanced the ML210-associated reduction in cell viability, supporting their functional involvement in malignant cellular behavior and stress-associated drug responses. Conclusion These findings identify an SLC7A11-linked lncRNA program associated with aggressive disease and immune-related transcriptional features suggestive of a functionally constrained tumor state in papillary thyroid carcinoma. Selected components of this program also contribute functionally to malignant cellular behavior and stress sensitivity. Rather than serving solely as a prognostic classifier, this lncRNA program may provide a framework for understanding the interplay between tumor stress adaptation and immune remodeling in thyroid carcinoma.