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.
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