Frontier review

Mechanisms and therapeutic applications of transketolase in regulating pentose phosphate metabolism and mitochondrial function

  • Wang Guanzhen ,
  • He Wenrui ,
  • Tong Xuemei
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  • Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 201318, China
Tong Xuemei, E-mail: xuemeitong@shsmu.edu.cn.

Received date: 2025-12-16

  Accepted date: 2026-01-12

  Online published: 2026-02-09

Supported by

National Natural Science Foundation of China(82425042,82330080,32371361)

Abstract

Transketolase (TKT) is a key metabolic enzyme in the non‑oxidative phase of the pentose phosphate pathway and is highly conserved across prokaryotes and eukaryotes. It catalyzes two reversible reactions that mediate the interconversion of phosphorylated sugars from three to seven carbons. Although TKT exhibits broad tissue distribution in mammals and is frequently upregulated across diverse malignancies, its definitive physiological roles and pathological implications remain mechanistically unresolved. Recent studies have shown that obesity and metabolic diseases, such as fatty liver disease,are characterized by hyperinsulinemia‑induced insulin resistance, with high insulin levels inducing TKT upregulation. As a master regulator of cellular pentose phosphate flux, TKT channels pentose‑containing metabolites into glycolytic processing, thereby accelerating pentose phosphate catabolism and reducing nucleoside and nucleotide pools. Emerging research has elucidated the roles of TKT in hepatocytes, adipocytes, regulatory T cells, and hepatocellular carcinoma, emphasizing its emerging role in pentose catabolism to coordinate nucleoside homeostasis with mitochondrial function, modulate nucleotide availability and genomic stability, and influence mitochondrial metabolite levels linked to DNA methylation. Collectively, these findings point to TKT as a promising metabolic target, offering novel preventive and therapeutic avenues for obesity, fatty liver disease, and hepatocellular carcinoma.

Cite this article

Wang Guanzhen , He Wenrui , Tong Xuemei . Mechanisms and therapeutic applications of transketolase in regulating pentose phosphate metabolism and mitochondrial function[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026 , 46(2) : 137 -142 . DOI: 10.3969/j.issn.1674-8115.2026.02.001

References

[1] TeSlaa T, Ralser M, Fan J, et al. The pentose phosphate pathway in health and disease[J]. Nat Metab, 2023, 5(8): 1275-1289.
[2] Chen Z Y, Zhang Y, Qian C, et al. The role of the pentose phosphate pathway in cardiovascular diseases[J]. Cardiovasc Drugs Ther, 2025. DOI: 10.1007/s10557-025-07788-w.
[3] Mao L Z, Dai Y H, Huang Y, et al. Studying the effect of light intensity on the photosynthetic mechanism of pepper leaf yellowing mutants by proteomics and phosphoproteomics[J]. Plant Sci, 2023, 334: 111763.
[4] Tonoli A, Dalby P A, Hailes H C, et al. Transketolase enzyme discovery and engineering[J]. Methods Enzymol, 2025, 722: 343-368.
[5] Ge T X, Yang J W, Zhou S H, et al. The role of the pentose phosphate pathway in diabetes and cancer[J]. Front Endocrinol, 2020, 11: 365.
[6] Li M L, Lu Y, Li Y K, et al. Transketolase deficiency protects the liver from DNA damage by increasing levels of ribose 5-phosphate and nucleotides[J]. Cancer Res, 2019, 79(14): 3689-3701.
[7] Xu Z P, Wawrousek E F, Piatigorsky J. Transketolase haploinsufficiency reduces adipose tissue and female fertility in mice[J]. Mol Cell Biol, 2002, 22(17): 6142-6147.
[8] Do A, Zahrawi F, Mehal W Z. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH)[J]. Nat Rev Drug Discov, 2025, 24(3): 171-189.
[9] Wang X B, Zhang L, Dong B N. Molecular mechanisms in MASLD/MASH-related HCC[J]. Hepatology, 2025, 82(5): 1303-1324.
[10] Hutchison A L, Tavaglione F, Romeo S, et al. Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): beyond insulin resistance[J]. J Hepatol, 2023, 79(6): 1524-1541.
[11] Tong L F, Chen Z B, Li Y Y, et al. Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity[J]. Cell Metab, 2024, 36(5): 1013-1029.e5.
[12] Tatsuta T, Scharwey M, Langer T. Mitochondrial lipid trafficking[J]. Trends Cell Biol, 2014, 24(1): 44-52.
[13] NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults[J]. Lancet, 2024, 403(10431): 1027-1050.
[14] Elmaleh-Sachs A, Schwartz J L, Bramante C T, et al. Obesity management in adults: a review[J]. JAMA, 2023, 330(20): 2000-2015.
[15] Kawai T, Autieri M V, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity[J]. Am J Physiol Cell Physiol, 2021, 320(3): C375-C391.
[16] Tian N, Liu Q, Li Y K, et al. Transketolase deficiency in adipose tissues protects mice from diet-induced obesity by promoting lipolysis[J]. Diabetes, 2020, 69(7): 1355-1367.
[17] Carpentier A C, Blondin D P, Haman F, et al. Brown adipose tissue: a translational perspective[J]. Endocr Rev, 2023, 44(2): 143-192.
[18] Ji Y N, Liu W, Zhu Y M, et al. Loss of transketolase promotes the anti-diabetic role of brown adipose tissues[J]. J Endocrinol, 2023, 256(3): e220047.
[19] Dikiy S, Rudensky A Y. Principles of regulatory T cell function[J]. Immunity, 2023, 56(2): 240-255.
[20] Coe D J, Kishore M, Marelli-Berg F. Metabolic regulation of regulatory T cell development and function[J]. Front Immunol, 2014, 5: 590.
[21] Liu Q, Zhu F M, Liu X N, et al. Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics[J]. Nat Metab, 2022, 4(5): 559-574.
[22] Xiao M T, Yang H, Xu W, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors[J]. Genes Dev, 2012, 26(12): 1326-1338.
[23] Shah A, Diculescu V C, Qureshi R, et al. Electrochemical behaviour of dimethyl-2-oxoglutarate on glassy carbon electrode[J]. Bioelectrochemistry, 2010, 77(2): 145-150.
[24] Hao S M, Meng Q F, Sun H H, et al. The role of transketolase in human cancer progression and therapy[J]. Biomed Pharmacother, 2022, 154: 113607.
[25] Llovet J M, Kelley R K, Villanueva A, et al. Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2021, 7(1): 6.
[26] Thomas A A, Le Huerou Y, de Meese J, et al. Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors[J]. Bioorg Med Chem Lett, 2008, 18(6): 2206-2210.
[27] Jia D, Liu C L, Zhu Z Y, et al. Novel transketolase inhibitor oroxylin A suppresses the non-oxidative pentose phosphate pathway and hepatocellular carcinoma tumour growth in mice and patient-derived organoids[J]. Clin Transl Med, 2022, 12(11): e1095.
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