Mitochondria play a central role in energy metabolism, redox homeostasis, and signal transduction in the thyroid cells. Increasing evidence indicates that mitochondrial DNA (mtDNA) mutations, copy number variations, and haplogroup-specific polymorphisms are closely associated with metabolic reprogramming and malignant progression of thyroid cancer. This review summarizes recent advances in the understanding of the impact of mitochondrial genome instability and metabolic plasticity on thyroid tumorigenesis. We discuss how mtDNA alterations disrupt oxidative phosphorylation (OXPHOS), trigger adaptive metabolic rewiring, and interact with key oncogenic pathways, such as HIF-1α, BRAFV600E mutations, and TSHR signaling in thyroid cancer. We also highlight the emerging diagnostic and therapeutic potential of mtDNA in thyroid cancer and outline current challenges and future research directions. Gaining deeper insights into the mitochondria–metabolism axis may provide novel biomarkers and metabolic intervention strategies for precision medicine in thyroid oncology.

Thyroid cancer (TC) is an endocrine malignant tumor with the fastest-growing incidence worldwide. It has complex pathological types and significant heterogeneity, with great differences in clinical prognosis among different subtypes. Among them, aggressive subtypes, such as radioiodine-refractory (RAI-R) TC and anaplastic thyroid cancer (ATC), have become a major challenge in current clinical diagnosis and treatment, due to limited treatment options and high risks of recurrence and metastasis. Tumor metabolic reprogramming is one of the characteristics of cancer, among which the Warburg effect plays a driving role. As a rate-limiting enzyme in the glycolytic pathway, pyruvate kinase M2 (PKM2), with its unique functional plasticity, has become a linchpin of glycolytic metabolism and malignant phenotypes of tumor cells. This article will systematically review the functional regulatory mechanisms of PKM2, its specific role in TC, and explore the targeted therapeutic strategies and research prospects of TC with PKM2, providing a new theoretical basis and potential plans for the clinical diagnosis and treatment.