Prognostic value and therapeutic potential of the cuproptosis-related gene LOXL2 in thyroid cancer

Background: Cuproptosis, a copper-dependent form of programmed cell death, has been implicated in the progression of various cancers. However, the role of LOXL2 - a cuproptosis-related gene (CRG) - and its prognostic value in thyroid cancer (THCA) remain largely unexplored. Methods: We systematically investigated the prognostic significance of CRGs in THCA through an integrative approach combining bioinformatics screening and experimental validation. Expression profiling of all identified CRGs was performed using The Cancer Genome Atlas (THCA cohort) to assess their transcriptional alterations and associations with patient prognosis. Pathway enrichment, immune infiltration, and drug sensitivity analyses were subsequently conducted to explore the functional relevance of these genes. CRGs exhibiting significant differential expression and prognostic correlation were selected for in vitro functional validation using EdU proliferation, CCK-8, and Transwell assays to elucidate the role of LOXL2 in THCA progression. Additionally, we evaluated the antitumor effects of cuproptosis inducers on THCA cells to explore the therapeutic potential of targeting cuproptosis. Results: Systematic expression analysis identified four CRGs (MT1A, MT1F, LOXL2, and MT1M) that were significantly dysregulated in THCA tissues compared to normal counterparts. Based on the expression patterns of these four genes, THCA patients were stratified into low-risk and high-risk groups. Notably, the high-risk group exhibited significantly lower immune scores and poorer overall survival. Pathway analysis revealed alterations in glycerolipid metabolism and oxidative phosphorylation in the high-risk group. Among the four genes, LOXL2 showed the strongest correlation with THCA prognosis. Functional assays demonstrated that LOXL2 knockdown significantly suppressed THCA cell viability, proliferation, migration, and invasion. Importantly, treatment with cuproptosis activators exerted potent anticancer effects against THCA cells. Conclusions: Our study indicates that LOXL2 may serve as a potential biomarker for cuproptosis-related pathways and represents a potential therapeutic target in THCA. Furthermore, our findings suggest that pharmacologically targeting cuproptosis-related genes may provide a promising therapeutic strategy for the management of THCA.