Lipid Metabolic Reprogramming in Thyroid Cancer: Systemic Biomarkers, Tumor Dependencies and Therapeutic Resistance

Lipid metabolic reprogramming is increasingly implicated in thyroid cancer progression and treatment resistance alongside circulating lipid associations are often conflated with tumor lipid dependency. A clinically useful synthesis must distinguish systemic lipid markers from intratumoral lipid flux before integrating them into mechanistic or therapeutic models. This critical narrative review integrates evidence across three connected layers: circulating lipid markers; tumor-intrinsic uptake, oxidation, synthesis, desaturation, cholesterol and oxysterol pathways; and immune-spatial niches involving macrophage lipid handling, APOE-associated polarization and ferroptosis-related lipid peroxidation. In papillary thyroid carcinoma, multi-omics and mechanistic studies implicate LPL-FATP2-CPT1A, PC-AKT/mTOR-SREBP1c-FASN and METTL16/YTHDC2/SCD1 programs in membrane remodeling, invasion-related behavior and recurrence risk stratification. In aggressive and anaplastic thyroid cancer, cholesterol synthesis signaling, fatty acid oxidation adaptation and SREBF1/SCD1-linked ferroptosis defense may contribute to resistance to radioiodine, radiotherapy, chemotherapy and BRAF/MEK inhibition. The current evidence is strongest for mechanistic and biomarker hypotheses; thyroid-cancer-specific prospective trials of lipid-directed treatment are lacking. Lipid metabolism therefore provides a framework for molecular stratification and treatment sensitization, but it does not currently justify nonspecific lipid lowering or routine lipid-targeted therapy. Translation will require paired blood and tumor lipidomics, spatial profiling, functional perturbation and biomarker-defined prospective studies.