Integrative analysis of lysosome-dependent cell death related molecular subtypes and prognosis prediction in papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, shows marked clinical heterogeneity despite generally favorable outcomes. Lysosome-dependent cell death (LDCD), a form of programmed death triggered by lysosomal membrane permeabilization, has emerged as a potential cancer therapy target, but its role in PTC remains unclear. METHODS: Transcriptomic data from public cohorts were analyzed to identify LDCD-related genes (LDCDRG) associated with PTC prognosis. Cox analysis and LASSO regression analyses were performed to construct a prognostic model. Immune landscape, drug sensitivity, and single-cell expression profiles were examined. Functional experiments were conducted in vitro to verify the biological effects of the key gene LMTK3 on PTC cell proliferation, viability, and invasion. RESULTS: Nineteen LDCDRG were differentially expressed between normal and tumor tissues, defining three molecular subtypes with distinct immune and prognostic profiles. A six-LDCDRG signature (LMTK3, MCM5, NXF1, TUBB4B, LIMCH1 and APH1B) effectively stratified patients into high- and low-risk groups with significantly different survival outcomes and acceptable predictive performance. High-risk patients showed reduced immune infiltration and lower predicted immunotherapy-related immune activity. LMTK3, the highest-risk gene, was highly expressed in PTC cells, and its knockdown suppressed proliferation and invasion in vitro. CONCLUSIONS: The established six-LDCDRG signature provides an exploratory tool for risk stratification and survival prediction, while LMTK3 emerges as potential target worthy of further investigation. These findings deepen our understanding of lysosome-dependent cell death in thyroid carcinogenesis and may provide insights into the development of personalized management strategies and novel treatment approaches for high-risk PTC patients.