Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Cell Death Discovery
  • View all journals
  • Search
  • My Account Login
  • Content Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • RSS feed
  1. nature
  2. cell death discovery
  3. review articles
  4. article
The molecular mechanisms and potential therapeutic implications of the crosstalk between DNA methylation and metabolic reprogramming in thyroid cancer
Download PDF
Download PDF
  • Review Article
  • Open access
  • Published: 25 February 2026

The molecular mechanisms and potential therapeutic implications of the crosstalk between DNA methylation and metabolic reprogramming in thyroid cancer

  • Tianying Zhang1,
  • Hengtong Han2,
  • Yating Zhang1,
  • Tingting Zhang1,
  • Libin Ma2,
  • Ze Yang2 &
  • …
  • Yong-xun Zhao  ORCID: orcid.org/0000-0003-3049-56252 

Cell Death Discovery , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer epigenetics
  • Cancer metabolism
  • DNA methylation
  • Oncogenesis
  • Thyroid cancer

Abstract

One of the fastest-growing malignant tumors in the world is thyroid cancer (TC), and there are currently no effective treatments for its aggressive subtypes, such as anaplastic carcinoma and radioactive iodine-refractory differentiated thyroid carcinoma. Recent investigations have shown that DNA methylation and metabolic reprogramming are not independent events, but rather create a closely interconnected, mutually reinforcing network of carcinogenic processes. On the one hand, metabolic reprogramming influences the methylation status of tumor suppressor genes and thyroid function genes by dynamically regulating the activity of DNA methyltransferases and demethylases through important metabolites (such as S-adenosylmethionine, or SAM, and α-KG) and oncogenic signaling pathways (like PI3K/AKT). Conversely, DNA methylation systematically remodels cellular glucose, lipid, and amino acid metabolism by directly silencing metabolic enzyme genes (such as FASN and GLS) and thyroid differentiation markers (such as NIS) to fulfill its proliferative demands. Tumor growth, treatment resistance, and the development of an immunosuppressive microenvironment are all fueled by this ongoing bidirectional interaction, which creates a self-reinforcing oncogenic cycle. As a result, the limitations of earlier discrete debates on DNA methylation or metabolic reprogramming are overcome in this review. To methodically clarify their crosstalk mechanisms, a theoretical framework based on the “DNA methylation-metabolism axis” is suggested. Additionally, it suggests multimodal therapy approaches that focus on this axis. Incorporating biomimetic delivery technologies, combined with epigenetic, metabolic, and immunotherapies, to lay the groundwork for comprehending TC causes and creating targeted treatments.

Similar content being viewed by others

Developing a thyroid cancer differentiation state classification system using deep residual networks and metabolic signature profiling

Article Open access 24 September 2025

Adding pieces to the puzzle of differentiated-to-anaplastic thyroid cancer evolution: the oncogene E2F7

Article Open access 10 February 2023

Circulating tumor cells: from new biological insights to clinical practice

Article Open access 02 September 2024

Data availability

Not Applicable.

References

  1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: A Cancer J Clin. 2023;73:17–48.

    Google Scholar 

  2. Voelker R. What Is Thyroid Cancer? JAMA. 2024;332:346.

    Google Scholar 

  3. Boucai L, Zafereo M, Cabanillas ME. Thyroid Cancer: A Review. JAMA. 2024;331:425–35.

    Google Scholar 

  4. Evans LK, Chen H, Taki Labib M, Cronkite DA, Yu AC, Ashendouek M, et al. Improved Survival of Advanced-Stage Anaplastic Thyroid Cancer With Systemic Therapy. The Laryngoscope [Internet]. 2025 Jan [cited 2025 Nov 13];135. Available from: https://pubmed.ncbi.nlm.nih.gov/39162326/.

  5. Volante M, Lam AK, Papotti M, Tallini G. Molecular pathology of poorly differentiated and anaplastic thyroid cancer: what do pathologists need to know?. Endocr Pathol. 2021;32:63–76.

    Google Scholar 

  6. Bao L, Xu T, Lu X, Huang P, Pan Z, Ge M. Metabolic reprogramming of thyroid cancer cells and crosstalk in their microenvironment. Front Oncol. 2021;11:773028.

    Google Scholar 

  7. Ju SH, Song M, Lim JY, Kang YE, Yi HS, Shong M. Metabolic Reprogramming in Thyroid Cancer. Endocrinol Metab. 2024;39:425–44.

    Google Scholar 

  8. Ge T, Gu X, Jia R, Ge S, Chai P, Zhuang A, et al. Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities. Cancer Commun. 2022;42:1049–82.

    Google Scholar 

  9. Zhang L, Feng Q, Wang J, Tan Z, Li Q, Ge M. Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities. Biochim Biophys Acta Rev Cancer. 2023;1878:188928.

    Google Scholar 

  10. Díaz-Gago S, Vicente-Gutiérrez J, Ruiz-Rodríguez JM, Calafell J, Álvarez-Álvarez A, Lasa M, et al. Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells. Autophagy. 2024;20:1383–97.

    Google Scholar 

  11. Zhang Y, Wang J. Targeting uptake transporters for cancer imaging and treatment. Acta Pharm Sin B. 2020;10:79–90.

    Google Scholar 

  12. Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2023;8:210.

    Google Scholar 

  13. Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19:81–92.

    Google Scholar 

  14. Hodges AJ, Hudson NO, Buck-Koehntop BA. Cys2His2 Zinc Finger Methyl-CpG Binding Proteins: Getting a Handle on Methylated DNA. J Mol Biol. 2020;432:1640–60.

    Google Scholar 

  15. Mensah IK, Norvil AB, AlAbdi L, McGovern S, Petell CJ, He M, et al. Misregulation of the expression and activity of DNA methyltransferases in cancer. NAR Cancer. 2021;3:zcab045.

    Google Scholar 

  16. Newar K, Abdulla AZ, Salari H, Fanchon E, Jost D. Dynamical modeling of the H3K27 epigenetic landscape in mouse embryonic stem cells. PLoS Comput Biol. 2022;18:e1010450.

    Google Scholar 

  17. Drohat AC, Coey CT. Role of Base Excision ‘Repair’ Enzymes in Erasing Epigenetic Marks from DNA. Chem Rev. 2016;116:12711–29.

    Google Scholar 

  18. Li J, Wang X. Functional roles of conserved lncRNAs and circRNAs in eukaryotes. Noncoding RNA Res. 2024;9:1271–9.

    Google Scholar 

  19. Bandargal S, Rajab M, Forest VI, Pusztaszeri MP, Hier MP, da Silva SD, et al. Characteristics of PTEN Mutation in Thyroid Tumours: A Retrospective Chart Review. Cancers. 2023;15:1575.

    Google Scholar 

  20. Wei F, Wu Y, Wang Z, Li Y, Wang J, Shao G, et al. Diagnostic significance of DNA methylation of PTEN and DAPK in thyroid tumors. Clin Endocrinol (Oxf). 2020;93:187–95.

    Google Scholar 

  21. Sun M, Zhao M, Li R, Zhang Y, Shi X, Ding C, et al. SHMT2 promotes papillary thyroid cancer metastasis through epigenetic activation of AKT signaling. Cell Death Dis. 2024;15:87.

    Google Scholar 

  22. Brait M, Loyo M, Rosenbaum E, Ostrow KL, Markova A, Papagerakis S, et al. Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer. Epigenetics. 2012;7:710–9.

    Google Scholar 

  23. Lee SJ, Lee MH, Kim DW, Lee S, Huang S, Ryu MJ, et al. Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway in papillary thyroid carcinoma. PLoS One. 2011;6:e16180.

    Google Scholar 

  24. Shou F, Xu F, Li G, Zhao Z, Mao Y, Yang F, et al. RASSF1A promoter methylation is associated with increased risk of thyroid cancer: a meta-analysis. Onco Targets Ther. 2017;10:247–57.

    Google Scholar 

  25. Stojanović Novković S, Šelemetjev S, Krajnović M, Božović A, Kožik B, Prosenc Zmrzljak U, et al. Implication of p16 Promoter Methylation, the BRAFV600E Mutation, and ETS1 Expression Determination on Papillary Thyroid Carcinoma Prognosis and High-Risk Patients’ Selection. Biomedicines. 2025;13:1583.

    Google Scholar 

  26. Cao YM, Gu J, Zhang YS, Wei WJ, Qu N, Wen D, et al. Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation. Oncol Rep. 2018;39:338–48.

    Google Scholar 

  27. Yang H, Zhou J, Mi J, Ma K, Fan Y, Ning J, et al. HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma. Oncol Rep. 2015;34:1681–91.

    Google Scholar 

  28. Xiao X, Chen M, Sang Y, Xue J, Jiang K, Chen Y, et al. Methylation-Mediated Silencing of ATF3 Promotes Thyroid Cancer Progression by Regulating Prognostic Genes in the MAPK and PI3K/AKT Pathways. Thyroid. 2023;33:1441–54.

    Google Scholar 

  29. Hong K, Cen K, Chen Q, Dai Y, Mai Y, Guo Y. Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy. Front Immunol. 2023;14:1128390.

    Google Scholar 

  30. Zhu X, Xue C, Kang X, Jia X, Wang L, Younis MH, et al. DNMT3B-mediated FAM111B methylation promotes papillary thyroid tumor glycolysis, growth and metastasis. Int J Biol Sci. 2022;18:4372–87.

    Google Scholar 

  31. Guan H, Ji M, Hou P, Liu Z, Wang C, Shan Z, et al. Hypermethylation of the DNA mismatch repair gene hMLH1 and its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer. Cancer. 2008;113:247–55.

    Google Scholar 

  32. Li S, Hu G, Chen Y, Sang Y, Tang Q, Liu R. TERT upstream promoter methylation regulates TERT expression and acts as a therapeutic target in TERT promoter mutation-negative thyroid cancer. Cancer Cell Int. 2024;24:271.

    Google Scholar 

  33. Wu M, Wei B, Duan SL, Liu M, Ou-Yang DJ, Huang P, et al. Methylation-Driven Gene PLAU as a Potential Prognostic Marker for Differential Thyroid Carcinoma. Front Cell Dev Biol. 2022;10:819484.

    Google Scholar 

  34. Khan MS, Pandith AA, Masoodi SR, Wani KA, Ul Hussain M, Mudassar S. Epigenetic silencing of TSHR gene in thyroid cancer patients in relation to their BRAF V600E mutation status. Endocrine. 2014;47:449–55.

    Google Scholar 

  35. Qu M, Wan S, Ren B, Wu H, Liu L, Shen H. Association between TSHR gene methylation and papillary thyroid cancer: a meta-analysis. Endocrine. 2020;69:508–15.

    Google Scholar 

  36. Ye C, Jiang N, Zheng J, Zhang S, Zhang J, Zhou J. Epigenetic therapy: Research progress of Decitabine in the treatment of solid tumors. Biochim Biophys Acta (BBA) - Rev Cancer. 2024;1879:189066.

    Google Scholar 

  37. Coelho RG, Cazarin J, de M, Cavalcanti de Albuquerque JPA, de Andrade BM, Carvalho DP. Differential glycolytic profile and Warburg effect in papillary thyroid carcinoma cell lines. Oncol Rep. 2016;36:3673–81.

    Google Scholar 

  38. Zarkesh M, Arab N, Abooshahab R, Heydarzadeh S, Sheikholeslami S, Nozhat Z, et al. CpG island status as an epigenetic alteration for NIS promoter in thyroid neoplasms; a cross-sectional study with a systematic review. Cancer Cell Int. 2022;22:310.

    Google Scholar 

  39. Oh JM, Ahn BC. Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS. Theranostics. 2021;11:6251–77.

    Google Scholar 

  40. Martínez-Reyes I, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021;21:669–80.

    Google Scholar 

  41. Fendt SM. 100 years of the Warburg effect: A cancer metabolism endeavor. Cell. 2024;187:3824–8.

    Google Scholar 

  42. Fagin JA, Krishnamoorthy GP, Landa I. Pathogenesis of cancers derived from thyroid follicular cells. Nat Rev Cancer. 2023;23:631–50.

    Google Scholar 

  43. Nagayama Y, Hamada K. Reprogramming of Cellular Metabolism and Its Therapeutic Applications in Thyroid Cancer. Metabolites. 2022;12:1214.

    Google Scholar 

  44. Liu CL, Yang PS, Wang TY, Huang SY, Kuo YH, Cheng SP. PGC1α downregulation and glycolytic phenotype in thyroid cancer. J Cancer. 2019;10:3819–29.

    Google Scholar 

  45. Liu CL, Hsu YC, Lee JJ, Chen MJ, Lin CH, Huang SY, et al. Targeting the pentose phosphate pathway increases reactive oxygen species and induces apoptosis in thyroid cancer cells. Mol Cell Endocrinol. 2020;499:110595.

    Google Scholar 

  46. Liu K, Du Y, Li H, Lin X. Identification of super-enhancer-associated transcription factors regulating glucose metabolism in poorly differentiated thyroid carcinoma. Genet Mol Biol. 2022;45:e20210370.

    Google Scholar 

  47. Liu C, Zhou X, Pan Y, Liu Y, Zhang Y. Pyruvate carboxylase promotes thyroid cancer aggressiveness through fatty acid synthesis. BMC Cancer. 2021;21:722.

    Google Scholar 

  48. Strickaert A, Corbet C, Spinette SA, Craciun L, Dom G, Andry G, et al. Reprogramming of Energy Metabolism: Increased Expression and Roles of Pyruvate Carboxylase in Papillary Thyroid Cancer. Thyroid. 2019;29:845–57.

    Google Scholar 

  49. Anderson NM, Mucka P, Kern JG, Feng H. The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2018;9:216–37.

    Google Scholar 

  50. Lee S, Rauch J, Kolch W. Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity. Int J Mol Sci. 2020;21:1102.

    Google Scholar 

  51. Yang Y, Wu J, Zhu H, Shi X, Liu J, Li Y, et al. Effect of hypoxia‑HIF‑1α‑periostin axis in thyroid cancer. Oncol Rep. 2024;51:57.

    Google Scholar 

  52. Song H, Qiu Z, Wang Y, Xi C, Zhang G, Sun Z, et al. HIF-1α/YAP signaling rewrites glucose/iodine metabolism program to promote papillary thyroid cancer progression. Int J Biol Sci. 2023;19:225–41.

    Google Scholar 

  53. Lukasiewicz M, Zwara A, Kowalski J, Mika A, Hellmann A. The role of lipid metabolism disorders in the development of thyroid cancer. Int J Mol Sci. 2024;25:7129.

    Google Scholar 

  54. von Roemeling CA, Marlow LA, Pinkerton AB, Crist A, Miller J, Tun HW, et al. Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl CoA desaturase 1 as a novel therapeutic target. J Clin Endocrinol Metab. 2015;100:E697–709.

    Google Scholar 

  55. Dube G, Tiamiou A, Bizet M, Boumahd Y, Gasmi I, Crake R, et al. Methylglyoxal: a novel upstream regulator of DNA methylation. J Exp Clin Cancer Res. 2023;42:78.

    Google Scholar 

  56. Chi J, Zhao J, Wei S, Li Y, Zhi J, Wang H, et al. A CRISPR-Cas9-Based Near-Infrared Upconversion-Activated DNA Methylation Editing System. ACS Appl Mater Interfaces. 2021;13:6043–52.

    Google Scholar 

  57. Valvo V, Iesato A, Kavanagh TR, Priolo C, Zsengeller Z, Pontecorvi A, et al. Fine-Tuning Lipid Metabolism by Targeting Mitochondria-Associated Acetyl-CoA-Carboxylase 2 in BRAF(V600E) Papillary Thyroid Carcinoma. Thyroid. 2021;31:1335–58.

    Google Scholar 

  58. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16:732–49.

    Google Scholar 

  59. Liang Z, He H, Zhang B, Kai Z, Zong L. Hypoxia expedites the progression of papillary thyroid carcinoma by promoting the CPT1A-mediated fatty acid oxidative pathway. Drug Dev Res. 2024;85:e22168.

    Google Scholar 

  60. Lu J, Zhang Y, Sun M, Ding C, Zhang L, Kong Y, et al. Multi-Omics Analysis of Fatty Acid Metabolism in Thyroid Carcinoma. Front Oncol. 2021;11:737127.

    Google Scholar 

  61. Tu Y, Chen Y, Mo L, Yan G, Xie J, Ji X, et al. Multi-omic analysis reveals a lipid metabolism gene signature and predicts prognosis and chemotherapy response in thyroid carcinoma. Cancer Med. 2025;14:e70819.

    Google Scholar 

  62. Häfliger P, Graff J, Rubin M, Stooss A, Dettmer MS, Altmann KH, et al. The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model. J Exp Clin Cancer Res. 2018;37:234.

    Google Scholar 

  63. Meng H, Xiao Z, Wang Q, Li D, Li Z. Genetic variations in amino acid metabolism-related genes are associated with risk of papillary thyroid carcinoma: a case-control study. BMC Endocr Disord. 2025;25:214.

    Google Scholar 

  64. Ducker GS, Rabinowitz JD. One-Carbon Metabolism in Health and Disease. Cell Metab. 2017;25:27–42.

    Google Scholar 

  65. Zhu X, Xuan Z, Chen J, Li Z, Zheng S, Song P. How DNA methylation affects the Warburg effect. Int J Biol Sci. 2020;16:2029–41.

    Google Scholar 

  66. Murugan AK, Bojdani E, Xing M. Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun. 2010;393:555–9.

    Google Scholar 

  67. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.

    Google Scholar 

  68. Wang P, Dong Q, Zhang C, Kuan PF, Liu Y, Jeck WR, et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32:3091–100.

    Google Scholar 

  69. Pusch S, Schweizer L, Beck AC, Lehmler JM, Weissert S, Balss J, et al. D-2-Hydroxyglutarate producing neo-enzymatic activity inversely correlates with frequency of the type of isocitrate dehydrogenase 1 mutations found in glioma. Acta Neuropathol Commun. 2014;2:19.

    Google Scholar 

  70. Qian J, Liu SX. CRISPR/dCas9-Tet1-Mediated DNA Methylation Editing. Bio Protoc. 2024;14:e4976.

    Google Scholar 

  71. Tao T, Yan J, Liao Z, Zhang W, Xu C, Li R. Oxidative low-density lipoprotein oxLDL induces pyroptosis in trophoblast cells HTR-8/Svneo by downregulating TET2. J Holist Integr Pharm. 2022;3:380–7.

    Google Scholar 

  72. Li Q, Wang W, Duan F, Wang Y, Chen S, Shi K, et al. DNMT3B Alleviates Liver Steatosis Induced by Chronic Low-grade LPS via Inhibiting CIDEA Expression. Cell Mol Gastroenterol Hepatol. 2024;17:59–77.

    Google Scholar 

  73. Cao K, Lv W, Wang X, Dong S, Liu X, Yang T, et al. Hypermethylation of Hepatic Mitochondrial ND6 Provokes Systemic Insulin Resistance. Adv Sci. 2021;8:2004507.

    Google Scholar 

  74. Zeng Q, Song J, Sun X, Wang D, Liao X, Ding Y, et al. A negative feedback loop between TET2 and leptin in adipocyte regulates body weight. Nat Commun. 2024;15:2825.

    Google Scholar 

  75. Fu R, Sun F, Wang W, Wang R, Zhang H, He X, et al. SHMT proteins: An emerging set of serine hydroxymethyltransferase in cancer. Cell Signal. 2025;135:111977.

    Google Scholar 

  76. Lee SE, Park S, Yi S, Choi NR, Lim MA, Chang JW, et al. Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses. Nat Commun. 2024;15:1163.

    Google Scholar 

  77. Maddocks ODK, Labuschagne CF, Adams PD, Vousden KH. Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. Mol Cell. 2016;61:210–21.

    Google Scholar 

  78. Schoultz E, Dahlberg J, Nilsson LM, Dzanan JJ, Carlsson T, Dahr N, et al. Involvement of KEAP1/NRF2 pathway in non-BRAF mutated squamous cell carcinoma of the thyroid. J Pathol. 2025;266:481–94.

    Google Scholar 

  79. Joshi K, Liu S, Breslin SJP, Zhang J. Mechanisms that regulate the activities of TET proteins. Cell Mol Life Sci. 2022;79:363.

    Google Scholar 

  80. Lopez-Serra P, Marcilla M, Villanueva A, Ramos-Fernandez A, Palau A, Leal L, et al. A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect. Nat Commun. 2014;5:3608.

    Google Scholar 

  81. Liu X, Fu J, Bi H, Ge A, Xia T, Liu Y, et al. DNA methylation of SFRP1, SFRP2, and WIF1 and prognosis of postoperative colorectal cancer patients. BMC Cancer. 2019;19:1212.

    Google Scholar 

  82. Veeck J, Niederacher D, An H, Klopocki E, Wiesmann F, Betz B, et al. Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis. Oncogene. 2006;25:3479–88.

    Google Scholar 

  83. Pate KT, Stringari C, Sprowl-Tanio S, Wang K, TeSlaa T, Hoverter NP, et al. Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J. 2014;33:1454–73.

    Google Scholar 

  84. Gou R, Chen S, Lei Y, Wu P, Chen X, Zhang Q. Hypoxia Inhibitor Improves Iodine Uptake Disorder in Thyroid Cancer Through the hsa_circ_0023990/miR-448/DNMT1/NIS Axis. Cancer Sci. 2025;116:2113–24.

    Google Scholar 

  85. Li Q, Wang Y, Meng X, Wang W, Duan F, Chen S, et al. METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism. Cell Mol Life Sci. 2024;81:81.

    Google Scholar 

  86. Pham DV, Park PH. Adiponectin triggers breast cancer cell death via fatty acid metabolic reprogramming. J Exp Clin Cancer Res. 2022;41:9.

    Google Scholar 

  87. Tan SK, Hougen HY, Merchan JR, Gonzalgo ML, Welford SM. Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets. Nat Rev Urol. 2023;20:48–60.

    Google Scholar 

  88. Zhang M, Yu L, Sun Y, Hao L, Bai J, Yuan X, et al. Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation. Int J Mol Sci. 2022;23:15603.

    Google Scholar 

  89. Nakamura MT, Yudell BE, Loor JJ. Regulation of energy metabolism by long-chain fatty acids. Prog Lipid Res. 2014;53:124–44.

    Google Scholar 

  90. Maréchal L, Laviolette M, Rodrigue-Way A, Sow B, Brochu M, Caron V, et al. The CD36-PPARγ Pathway in Metabolic Disorders. Int J Mol Sci. 2018;19:1529.

    Google Scholar 

  91. Christiansen C, Tomlinson M, Eliot M, Nilsson E, Costeira R, Xia Y, et al. Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers. Genome Med. 2022;14:75.

    Google Scholar 

  92. Bott AJ, Peng IC, Fan Y, Faubert B, Zhao L, Li J, et al. Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation. Cell Metab. 2015;22:1068–77.

    Google Scholar 

  93. Dong J, Xiao D, Zhao Z, Ren P, Li C, Hu Y, et al. Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism. Oncogenesis. 2017;6:e356.

    Google Scholar 

  94. Zhang K, Wang J, He Z, Qiu X, Sa R, Chen L. Epigenetic Targets and Their Inhibitors in Thyroid Cancer Treatment. Pharmaceuticals. 2023;16.

  95. Provenzano MJ, Fitzgerald MP, Krager K, Domann FE. Increased iodine uptake in thyroid carcinoma after treatment with sodium butyrate and decitabine (5-Aza-dC). Otolaryngol–head Neck Surg. 2007;137:722–8.

    Google Scholar 

  96. Choi YW, Kim HJ, Kim YH, Park SH, Chwae YJ, Lee J, et al. B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1. Exp Mol Med. 2014;46:e120–e120.

    Google Scholar 

  97. Laranjeira ABA, Hollingshead MG, Nguyen D, Kinders RJ, Doroshow JH, Yang SX. DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors. Sci Rep. 2023;13:5964.

    Google Scholar 

  98. Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2’-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 2000;60:6039–44.

    Google Scholar 

  99. Vitale G, Dicitore A, Pepe D, Gentilini D, Grassi ES, Borghi MO, et al. Synergistic activity of everolimus and 5-aza-2’-deoxycytidine in medullary thyroid carcinoma cell lines. Mol Oncol. 2017;11:1007–22.

    Google Scholar 

  100. Zhang G, Gao X, Zhao X, Wu H, Yan M, Li Y, et al. Decitabine inhibits the proliferation of human T-cell acute lymphoblastic leukemia molt4 cells and promotes apoptosis partly by regulating the PI3K/AKT/mTOR pathway. Oncol Lett. 2021;21:340.

    Google Scholar 

  101. Hasegawa T, Adachi R, Iwakata H, Takeno T, Sato K, Sakamaki T. ErbB2 signaling epigenetically suppresses microRNA-205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer. FEBS Open Bio. 2017;7:1154–65.

    Google Scholar 

  102. Gonçalves J, Emmons MF, Faião-Flores F, Aplin AE, Harbour JW, Licht JD, et al. Decitabine limits escape from MEK inhibition in uveal melanoma. Pigment Cell Melanoma Res. 2020;33:507–14.

    Google Scholar 

  103. Arosio G, Sharma GG, Villa M, Mauri M, Crespiatico I, Fontana D, et al. Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma. Cancers. 2021;13:4422.

    Google Scholar 

  104. Wang Y, Tong C, Dai H, Wu Z, Han X, Guo Y, et al. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming. Nat Commun. 2021;12:409.

    Google Scholar 

  105. Wen SS, Wu YJ, Wang JY, Ni ZX, Dong S, Xie XJ, et al. BRAFV600E/p-ERK/p-DRP1(Ser616) Promotes Tumor Progression and Reprogramming of Glucose Metabolism in Papillary Thyroid Cancer. Thyroid. 2024;34:1246–59.

    Google Scholar 

  106. Zhao B, Aggarwal A, Im SY, Viswanathan K, Landa I, Nehs MA. Effect of Lactate Export Inhibition on Anaplastic Thyroid Cancer Growth and Metabolism. J Am Coll Surg. 2022;234:1044–50.

    Google Scholar 

  107. Halford S, Veal GJ, Wedge SR, Payne GS, Bacon CM, Sloan P, et al. A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer. Clin Cancer Res. 2023;29:1429–39.

    Google Scholar 

  108. Mehibel M, Ortiz-Martinez F, Voelxen N, Boyers A, Chadwick A, Telfer BA, et al. Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters. Sci Rep. 2018;8:16804.

    Google Scholar 

  109. Huang T, Feng Q, Wang Z, Li W, Sun Z, Wilhelm J, et al. Tumor-Targeted Inhibition of Monocarboxylate Transporter 1 Improves T-Cell Immunotherapy of Solid Tumors. Adv Health Mater. 2021;10:e2000549.

    Google Scholar 

  110. Schlaepfer IR, Joshi M. CPT1A-mediated Fat Oxidation, Mechanisms, and Therapeutic Potential. Endocrinology. 2020;161:bqz046.

    Google Scholar 

  111. McGuffee RM, McCommis KS, Ford DA. Etomoxir: an old dog with new tricks. J Lipid Res. 2024;65:100604.

    Google Scholar 

  112. Lanman TA, Youssef G, Huang R, Rahman R, DeSalvo M, Flood T, et al. Ivosidenib for the treatment of IDH1-mutant glioma, grades 2-4: Tolerability, predictors of response, and outcomes. Neurooncol Adv. 2025;7:vdae227.

    Google Scholar 

  113. Rothenberg SM, McFadden DG, Palmer EL, Daniels GH, Wirth LJ. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res. 2015;21:1028–35.

    Google Scholar 

  114. Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. J Clin Oncol. 2018;36:7–13.

    Google Scholar 

  115. Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368:623–32.

    Google Scholar 

  116. Schneider TC, de Wit D, Links TP, van Erp NP, van der Hoeven JJM, Gelderblom H, et al. Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial. J Clin Endocrinol Metab. 2017;102:698–707.

    Google Scholar 

  117. de Wit D, Schneider TC, Moes DJaR, Roozen CFM, den Hartigh J, Gelderblom H, et al. Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer. Cancer Chemother Pharm. 2016;78:63–71.

    Google Scholar 

  118. Lin QY, Qi QL, Hou S, Chen Z, Jiang N, Zhang L, et al. Silencing of AHNAK2 restricts thyroid carcinoma progression by inhibiting the Wnt/β-catenin pathway. Neoplasma. 2021;68:1063–71.

    Google Scholar 

  119. Zou Z, Zhong L. Anaplastic thyroid cancer: Genetic roles, targeted therapy, and immunotherapy. Genes Dis. 2025;12:101403.

    Google Scholar 

  120. Sheikholeslami S, Zarif-Yeganeh M, Farashi S, Azizi F, Kia SK, Teimoori-Toolabi L, et al. Promoter Methylation of Tumor Suppressors in Thyroid Carcinoma: A Systematic Review. Iran J Public Health. 2021;50:2461–72.

    Google Scholar 

  121. Yuan J, Dong X, Yap J, Hu J. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol. 2020;13:113.

    Google Scholar 

  122. Zeng JD, Wu WKK, Wang HY, Li XX. Serine and one-carbon metabolism, a bridge that links mTOR signaling and DNA methylation in cancer. Pharmacol Res. 2019;149:104352.

    Google Scholar 

  123. Li M, Wu C, Yang Y, Zheng M, Yu S, Wang J, et al. 3-Phosphoglycerate dehydrogenase: a potential target for cancer treatment. Cell Oncol. 2021;44:541–56.

    Google Scholar 

  124. Tajan M, Hennequart M, Cheung EC, Zani F, Hock AK, Legrave N, et al. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat Commun. 2021;12:366.

    Google Scholar 

  125. Orvain C, Tavitian S, Mediavilla C, Boyer F, Santagostino A, Venton G, et al. Outcome of patients with accelerated and blast-phase myeloproliferative neoplasms not eligible for intensive chemotherapy or allogeneic hematopoietic cell transplantation treated by azacitidine alone or in combination-A FIM study. Hemasphere. 2025;9:e70202.

    Google Scholar 

  126. Mina A, McGraw KL, Cunningham L, Kim N, Jen EY, Calvo KR, et al. Advancing drug development in myelodysplastic syndromes. Blood Adv. 2025;9:1095–104.

    Google Scholar 

  127. Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022;386:1519–31.

    Google Scholar 

  128. Harba D, Corell A, Mansouri A, Brandal P, Blomstrand M, Jakola AS. A scoping review of proton radiation therapy and mutant-isocitrate dehydrogenase-inhibitors in IDH mutated lower-grade gliomas: pushing beyond surrogate end-points. Acta Neurochir (Wien). 2025;167:196.

    Google Scholar 

  129. Zhang J, Hu L, Wang H, Zhi J, Hou X, Wu Y, et al. Functional analysis and clinical significance of the isocitrate dehydrogenase 2 gene in papillary thyroid carcinoma. Cancer Manag Res. 2019;11:3765–77.

    Google Scholar 

  130. Khan ZM, Real AM, Marsiglia WM, Chow A, Duffy ME, Yerabolu JR, et al. Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature. 2020;588:509–14.

    Google Scholar 

  131. Klieser E, Neumayer B, Di Fazio P, Mayr C, Neureiter D, Kiesslich T. HDACs as an emerging target in endocrine tumors: a comprehensive review. Expert Rev Endocrinol Metab. 2023;18:143–54.

    Google Scholar 

  132. Hamidi S, Ning MS, Phan J, Zafereo ME, Gule-Monroe MK, Dadu R. Recurrent Poorly Differentiated Thyroid Cancer Successfully Treated With Radiation and Immunotherapy. JCEM Case Rep. 2025;3:luaf015.

    Google Scholar 

  133. Li G, Hu J, Cho C, Cui J, Li A, Ren P, et al. Everolimus combined with PD-1 blockade inhibits progression of triple-negative breast cancer. Cellular signalling [Internet]. 2023 Sept [cited 2025 Mar 1];109. Available from: https://pubmed.ncbi.nlm.nih.gov/37257766/.

  134. Dierks C, Seufert J, Aumann K, Ruf J, Klein C, Kiefer S, et al. Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma. Thyroid. 2021;31:1076–85.

    Google Scholar 

  135. Ahmad U, Islam A, Khan MM, Akhtar J. Nanotechnology-driven Epigenetic Cancer Therapy: Precision Delivery and Sustained Release of DNA Methylation Modulators. Yale J Biol Med. 2025;98:227–35.

    Google Scholar 

  136. Yang CL, Chao YJ, Wang HC, Hou YC, Chen CG, Chang CC, et al. Local ablation of gastric cancer by reconstituted apolipoprotein B lipoparticles carrying epigenetic drugs. Nanomedicine. 2021;37:102450.

    Google Scholar 

  137. Niu Q, Liu Y, Zheng Y, Tang Z, Qian Y, Qi R, et al. Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics. Acta Pharm Sin B. 2022;12:4458–71.

    Google Scholar 

  138. Kapoor DU, Patel G, Prajapati BG. Nanomedicine-Based Treatments for Rare and Aggressive Ocular Cancers: Advances in Drug Delivery. Curr Treat Options Oncol. 2025;26:569–86.

    Google Scholar 

  139. Zhao X, Qin X, Wang R, Wang Y, He Y, Wang Y, et al. An Epigenetic Nanoagonist Facilitates T Cell Priming, Recruitment, and Reinvigoration in Tumors Resistant to PD-L1 Therapy. Adv Mater. 2025;e02800.

  140. Tost J, Gut IG. DNA methylation analysis by pyrosequencing. Nat Protoc. 2007;2:2265–75.

    Google Scholar 

  141. Hattori N, Liu YY, Ushijima T. DNA Methylation Analysis. Methods Mol Biol. 2023;2691:165–83.

    Google Scholar 

  142. Schubert L, Mariko ML, Clerc J, Huillard O, Groussin L. MAPK Pathway Inhibitors in Thyroid Cancer: Preclinical and Clinical Data. Cancers (Basel). 2023;15:710.

    Google Scholar 

  143. Subbiah V, Kreitman RJ, Wainberg ZA, Gazzah A, Lassen U, Stein A, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med. 2023;29:1103–12.

    Google Scholar 

  144. Weber M, Kersting D, Riemann B, Brandenburg T, Führer-Sakel D, Grünwald F, et al. Enhancing Radioiodine Incorporation into Radioiodine-Refractory Thyroid Cancer with MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study. Clin Cancer Res. 2022;28:4194–202.

    Google Scholar 

  145. Dorman A, Shendler G, Warshavsky A, Muhanna N, Horowitz G, Furman LK, et al. Surgical Outcomes Following Neoadjuvant-targeted Therapy For Advanced Differentiated Thyroid Cancer-real-world Data. Clin Endocrinol. 2025 Nov;

  146. Busaidy NL, Konda B, Wei L, Wirth LJ, Devine C, Daniels GA, et al. Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. Thyroid. 2022;32:1184–92.

    Google Scholar 

  147. Zhao K, Chen L. Immune checkpoint inhibitors against thyroid cancer. Int J Surg. 2025;111:7346–9.

    Google Scholar 

  148. Basté N, Mora M, Grau JJ. Emerging systemic antitarget treatment for differentiated thyroid carcinoma. Curr Opin Oncol. 2021;33:184–95.

    Google Scholar 

  149. Murugan AK, Qasem E, Al-Hindi H, Alzahrani AS. Analysis of ALK, IDH1, IDH2 and MMP8 somatic mutations in differentiated thyroid cancers. Mol Clin Oncol. 2021;15:210.

    Google Scholar 

  150. Lee AV, Nestler KA, Chiappinelli KB. Therapeutic targeting of DNA methylation alterations in cancer. Pharm Ther. 2024;258:108640.

    Google Scholar 

  151. Vishakha S, Navneesh N, Kurmi BD, Gupta GD, Verma SK, Jain A, et al. An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021). Anticancer Agents Med Chem. 2024;24:590–626.

    Google Scholar 

  152. Ji X, Liang W, Lv G, Ding C, Lai H, Li L, et al. Efficacy and safety of targeted therapeutics for patients with radioiodine-refractory differentiated thyroid cancer: Systematic review and network meta-analysis. Front Pharm. 2022;13:933648.

    Google Scholar 

  153. Ho AL, Dedecjus M, Wirth LJ, Tuttle RM, Inabnet WB, Tennvall J, et al. Selumetinib Plus Adjuvant Radioactive Iodine in Patients With High-Risk Differentiated Thyroid Cancer: A Phase III, Randomized, Placebo-Controlled Trial (ASTRA). J Clin Oncol. 2022;40:1870–8.

    Google Scholar 

  154. Iyer PC, Dadu R, Gule-Monroe M, Busaidy NL, Ferrarotto R, Habra MA, et al. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J Immunother Cancer. 2018;6:68.

    Google Scholar 

  155. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75:10–45.

    Google Scholar 

  156. Gunda V, Bucur O, Varnau J, Vanden Borre P, Bernasconi MJ, Khosravi-Far R, et al. Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways. Cell Death Dis. 2014;5:e1104.

    Google Scholar 

  157. Huang X, Kong G, Li Y, Zhu W, Xu H, Zhang X, et al. Decitabine and 5-azacitidine both alleviate LPS induced ARDS through anti-inflammatory/antioxidant activity and protection of glycocalyx and inhibition of MAPK pathways in mice. Biomed Pharmacother. 2016;84:447–53.

    Google Scholar 

Download references

Acknowledgements

The authors acknowledge that all figures were supported by BioRender (https://biorender.com).

Funding

This work was supported by the following grants: Natural Science Foundation of Gansu Province, China [No. 17JR5RA272; No. 22JR5RA923] and Research Fund project of The First Hospital of Lanzhou University [No. Ldyyyn2021-120; No. Ldyyyn2020-98; No. Ldyyyn2021-30].

Author information

Authors and Affiliations

  1. The First School of Clinical Medicine, Lanzhou University, Lanzhou, China

    Tianying Zhang, Yating Zhang & Tingting Zhang

  2. The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China

    Hengtong Han, Libin Ma, Ze Yang & Yong-xun Zhao

Authors
  1. Tianying Zhang
    View author publications

    Search author on:PubMed Google Scholar

  2. Hengtong Han
    View author publications

    Search author on:PubMed Google Scholar

  3. Yating Zhang
    View author publications

    Search author on:PubMed Google Scholar

  4. Tingting Zhang
    View author publications

    Search author on:PubMed Google Scholar

  5. Libin Ma
    View author publications

    Search author on:PubMed Google Scholar

  6. Ze Yang
    View author publications

    Search author on:PubMed Google Scholar

  7. Yong-xun Zhao
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Tianying Zhang–Writing–Original Draft, Conceptualization. Hengtong Han–Writing–Review & Editing. Yating Zhang–Supervision. Tingting Zhang–Supervision. Libin Ma–Supervision. Ze Yang–Supervision. Yong-xun Zhao–Writing–Review & Editing, Conceptualization, Supervision. All authors have read and agreed to the final version of the manuscript.

Corresponding author

Correspondence to Yong-xun Zhao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

Not Applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, T., Han, H., Zhang, Y. et al. The molecular mechanisms and potential therapeutic implications of the crosstalk between DNA methylation and metabolic reprogramming in thyroid cancer. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02981-8

Download citation

  • Received: 03 September 2025

  • Revised: 21 January 2026

  • Accepted: 16 February 2026

  • Published: 25 February 2026

  • DOI: https://doi.org/10.1038/s41420-026-02981-8

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Download PDF

Advertisement

Explore content

  • Research articles
  • Reviews & Analysis
  • News & Comment
  • Collections
  • Follow us on X
  • Sign up for alerts
  • RSS feed

About the journal

  • Aims & Scope
  • Journal Information
  • About the Editors
  • Contact
  • About the Partner
  • Upcoming Conferences
  • Open Access Fees and Funding

Publish with us

  • For Authors & Referees
  • Language editing services
  • Open access funding
  • Submit manuscript

Search

Advanced search

Quick links

  • Explore articles by subject
  • Find a job
  • Guide to authors
  • Editorial policies

Cell Death Discovery (Cell Death Discov.)

ISSN 2058-7716 (online)

nature.com sitemap

About Nature Portfolio

  • About us
  • Press releases
  • Press office
  • Contact us

Discover content

  • Journals A-Z
  • Articles by subject
  • protocols.io
  • Nature Index

Publishing policies

  • Nature portfolio policies
  • Open access

Author & Researcher services

  • Reprints & permissions
  • Research data
  • Language editing
  • Scientific editing
  • Nature Masterclasses
  • Research Solutions

Libraries & institutions

  • Librarian service & tools
  • Librarian portal
  • Open research
  • Recommend to library

Advertising & partnerships

  • Advertising
  • Partnerships & Services
  • Media kits
  • Branded content

Professional development

  • Nature Awards
  • Nature Careers
  • Nature Conferences

Regional websites

  • Nature Africa
  • Nature China
  • Nature India
  • Nature Japan
  • Nature Middle East
  • Privacy Policy
  • Use of cookies
  • Legal notice
  • Accessibility statement
  • Terms & Conditions
  • Your US state privacy rights
Springer Nature

© 2026 Springer Nature Limited