Research progress on <i>PFKFB3</i> gene in fundus neovascular diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Ping ¹ , Cui Kaixuan ^2,3 , Liu Yaling ^2,3 , Zhao Xinyu ^2,3 , Wu Zhenquan ^2,3 , Yu Zhen ^2,3 , Wei Peiling ^2,3 ,  Zhang Guoming ^2,3

1. School of Clinical Medicine, Shandong Second Medical University, Weifang 261000, China;
2. Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University, Shenzhen 518040, China;
3. Second Clinical Medical College, Jinan University, Shenzhen 518000, China;

Corresponding author：

Zhang Guoming, Email: zhangguoming@sz-eyes.com

Keywords：

PFKFB3 gene; Fundus neovascular diseases; Glycolysis; Review

DOI：

10.3760/cma.j.cn511434-20250116-00026

Video：

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Abstract Full text Figures/Tables Video References Cited by

Fundus neovascularization is a significant cause of ocular diseases, mainly including retinal neovascularization and choroidal neovascularization. Anti-vascular endothelial growth factor therapy, though effective, has limitations such as a short half-life, non-responsiveness, and drug resistance. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key regulator of glycolysis, affects the generation of pathological blood vessels by modulating the metabolism of vascular endothelial cells. Small molecule inhibitors targeting PFKFB3 protein have been confirmed in animal and cell models to significantly inhibit pathological angiogenesis, showing good therapeutic potential. However, most of them are still in the preclinical research stage. In the future, it is necessary to further investigate the mechanism of PFKFB3 gene, optimize the specificity and safety of the inhibitors, and explore the effects of combining them with existing therapies, so as to provide new strategies for the treatment of fundus neovascular diseases.

Citation： Liu Ping, Cui Kaixuan, Liu Yaling, Zhao Xinyu, Wu Zhenquan, Yu Zhen, Wei Peiling, Zhang Guoming. Research progress on PFKFB3 gene in fundus neovascular diseases. Chinese Journal of Ocular Fundus Diseases, 2025, 41(10): 812-818. doi: 10.3760/cma.j.cn511434-20250116-00026 Copy

1.
2.
3.
4.
5.
6.
7.	Zhou ZY, Wang L, Wang YS, et al. PFKFB3: a potential key to ocular angiogenesis[J/OL]. Front Cell Dev Biol, 2021, 9: 628317[2021-04-11]. https://pubmed.ncbi.nlm.nih.gov/33777937/. DOI: 10.3389/fcell.2021.628317.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.	Shi L, Pan H, Liu Z, et al. Roles of PFKFB3 in cancer[J/OL]. Signal Transduct Target Ther, 2017, 2: 17044[2017-11-24]. https://pubmed.ncbi.nlm.nih.gov/29263928/. DOI: 10.1038/sigtrans.2017.44.
24.
25.
26.
27.
28.	Wu Y, Zhang MH, Xue Y, et al. Effect of microRNA-26a on vascular endothelial cell injury caused by lower extremity ischemia-reperfusion injury through the AMPK pathway by targeting PFKFB3[J]. J Cell Physiol, 2019, 234(3): 2916-2928. DOI: 10.1002/jcp.27108.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.	Leal-Esteban LC, Fajas L. Cell cycle regulators in cancer cell metabolism[J/OL]. Biochim Biophys Acta Mol Basis Dis, 2020, 1866(5): 165715[2020-05-01]. https://pubmed.ncbi.nlm.nih.gov/32035102/. DOI: 10.1016/j.bbadis.2020.165715.
41.
42.
43.
44.
45.	Draoui N, de Zeeuw P, Carmeliet P. Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism[J/OL]. Open Biol, 2017, 7(12): 170219[2017-12-01]. https://pubmed.ncbi.nlm.nih.gov/29263247/. DOI: 10.1098/rsob.170219.
46.	Zhou L, Li J, Wang J, et al. Pathogenic role of PFKFB3 in endothelial inflammatory diseases[J/OL]. Front Mol Biosci, 2024, 11: 1454456[2024-09-10]. https://pubmed.ncbi.nlm.nih.gov/39318551/. DOI: 10.3389/fmolb.2024.1454456.
47.
48.	Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity[J/OL]. Cochrane Database Syst Rev, 2018, 1(1): Cd009734[2018-01-08]. https://pubmed.ncbi.nlm.nih.gov/29308602/. DOI: 10.1002/14651858.CD009734.pub2.
49.
50.
51.	Wang Y, Xie L, Zhu M, et al. Shikonin alleviates choroidal neovascularization by inhibiting proangiogenic factor production from infiltrating macrophages[J/OL]. Exp Eye Res, 2021, 213: 108823[2021-11-06]. https://pubmed.ncbi.nlm.nih.gov/34752817/. DOI: 10.1016/j.exer.2021.108823.
52.
53.
54.
55.	Zhou N, Liu L, Li Q. IL1R2 promotes retinal angiogenesis to participate in retinopathy of prematurity by activating the HIF1α/PFKFB3 pathway[J/OL]. Exp Eye Res, 2024, 239: 109750[2023-12-13]. https://pubmed.ncbi.nlm.nih.gov/38097102/. DOI: 10.1016/j.exer.2023.109750.
56.	Liu Z, Xu J, Ma Q, et al. Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche[J/OL]. Sci Transl Med, 2020, 12(555): 1371[2020-08-05]. https://pubmed.ncbi.nlm.nih.gov/32759274/. DOI: 10.1126/scitranslmed.aay1371.
57.
58.	Wong TY, Cheung CM, Larsen M, et al. Diabetic retinopathy[J/OL]. Nat Rev Dis Primers, 2016, 2: 16013[2016-03-17]. https://pubmed.ncbi.nlm.nih.gov/27159554/. DOI: 10.1038/nrdp.2016.12.
59.	Nawaz IM, Rezzola S, Cancarini A, et al. Human vitreous in proliferative diabetic retinopathy: characterization and translational implications[J/OL]. Prog Retin Eye Res, 2019, 72: 100756[2019-04-02]. https://pubmed.ncbi.nlm.nih.gov/30951889/. DOI: 10.1016/j.preteyeres.2019.03.002.
60.
61.
62.
63.
64.	Blasiak J, Hyttinen JMT, Szczepanska J, et al. Potential of long non-coding RNAs in age-related macular degeneration[J/OL]. Int J Mol Sci, 2021, 22(17): 9178[2021-08-25]. https://pubmed.ncbi.nlm.nih.gov/34502084/. DOI: 10.3390/ijms22179178.
65.
66.	Brodzka S, Baszyński J, Rektor K, et al. The role of glutathione in age-related macular degeneration (AMD)[J/OL]. Int J Mol Sci, 2024, 25(8): 4158[2024-04-09]. https://pubmed.ncbi.nlm.nih.gov/38673745/. DOI: 10.3390/ijms25084158.
67.
68.
69.
70.
71.	Emini Veseli B, Van Wielendaele P, Delibegovic M, et al. The PFKFB3 inhibitor AZ67 inhibits angiogenesis independently of glycolysis inhibition[J/OL]. Int J Mol Sci, 2021, 22(11): 5970[2021-05-31]. https://pubmed.ncbi.nlm.nih.gov/34073144/. DOI: 10.3390/ijms22115970.
72.
73.	Galindo CM, Oliveira Ganzella FA, Klassen G, et al. Nuances of PFKFB3 signaling in breast cancer[J/OL]. Clin Breast Cancer, 2022, 22(4): e604-e614[2022-01-15]. https://pubmed.ncbi.nlm.nih.gov/35135735/. DOI: 10.1016/j.clbc.2022.01.002.
74.	De Oliveira T, Goldhardt T, Edelmann M, et al. Effects of the novel PFKFB3 inhibitor KAN0438757 on colorectal cancer cells and its systemic toxicity evaluation In vivo[J/OL]. Cancers, 2021, 13(5): 1011[2021-02-28]. https://pubmed.ncbi.nlm.nih.gov/33671096/. DOI: 10.3390/cancers13051011.
75.
76.	Xu J, Wang L, Yang Q, et al. Deficiency of myeloid PFKFB3 protects mice from lung edema and cardiac dysfunction in LPS-induced endotoxemia[J/OL]. Front Cardiovasc Med, 2021, 8: 745810[2021-09-29]. https://pubmed.ncbi.nlm.nih.gov/34660743/. DOI: 10.3389/fcvm.2021.745810.
77.	Seo M, Kim JD, Neau D, et al. Structure-based development of small molecule PFKFB3 inhibitors: a framework for potential cancer therapeutic agents targeting the Warburg effect[J/OL]. PLoS One, 2011, 6(9): e24179[2011-09-21]. https://pubmed.ncbi.nlm.nih.gov/21957443/. DOI: 10.1371/journal.pone.0024179.
78.	Abdali A, Baci D, Damiani I, et al. In vitro angiogenesis inhibition with selective compounds targeting the key glycolytic enzyme PFKFB3[J/OL]. Pharmacol Res, 2021, 168: 105592[2021-04-01]. https://pubmed.ncbi.nlm.nih.gov/33813027/. DOI: 10.1016/j.phrs.2021.105592.

1.
2.
3.
4.
5.
6.
7. Zhou ZY, Wang L, Wang YS, et al. PFKFB3: a potential key to ocular angiogenesis[J/OL]. Front Cell Dev Biol, 2021, 9: 628317[2021-04-11]. https://pubmed.ncbi.nlm.nih.gov/33777937/. DOI: 10.3389/fcell.2021.628317.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23. Shi L, Pan H, Liu Z, et al. Roles of PFKFB3 in cancer[J/OL]. Signal Transduct Target Ther, 2017, 2: 17044[2017-11-24]. https://pubmed.ncbi.nlm.nih.gov/29263928/. DOI: 10.1038/sigtrans.2017.44.
24.
25.
26.
27.
28. Wu Y, Zhang MH, Xue Y, et al. Effect of microRNA-26a on vascular endothelial cell injury caused by lower extremity ischemia-reperfusion injury through the AMPK pathway by targeting PFKFB3[J]. J Cell Physiol, 2019, 234(3): 2916-2928. DOI: 10.1002/jcp.27108.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40. Leal-Esteban LC, Fajas L. Cell cycle regulators in cancer cell metabolism[J/OL]. Biochim Biophys Acta Mol Basis Dis, 2020, 1866(5): 165715[2020-05-01]. https://pubmed.ncbi.nlm.nih.gov/32035102/. DOI: 10.1016/j.bbadis.2020.165715.
41.
42.
43.
44.
45. Draoui N, de Zeeuw P, Carmeliet P. Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism[J/OL]. Open Biol, 2017, 7(12): 170219[2017-12-01]. https://pubmed.ncbi.nlm.nih.gov/29263247/. DOI: 10.1098/rsob.170219.
46. Zhou L, Li J, Wang J, et al. Pathogenic role of PFKFB3 in endothelial inflammatory diseases[J/OL]. Front Mol Biosci, 2024, 11: 1454456[2024-09-10]. https://pubmed.ncbi.nlm.nih.gov/39318551/. DOI: 10.3389/fmolb.2024.1454456.
47.
48. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity[J/OL]. Cochrane Database Syst Rev, 2018, 1(1): Cd009734[2018-01-08]. https://pubmed.ncbi.nlm.nih.gov/29308602/. DOI: 10.1002/14651858.CD009734.pub2.
49.
50.
51. Wang Y, Xie L, Zhu M, et al. Shikonin alleviates choroidal neovascularization by inhibiting proangiogenic factor production from infiltrating macrophages[J/OL]. Exp Eye Res, 2021, 213: 108823[2021-11-06]. https://pubmed.ncbi.nlm.nih.gov/34752817/. DOI: 10.1016/j.exer.2021.108823.
52.
53.
54.
55. Zhou N, Liu L, Li Q. IL1R2 promotes retinal angiogenesis to participate in retinopathy of prematurity by activating the HIF1α/PFKFB3 pathway[J/OL]. Exp Eye Res, 2024, 239: 109750[2023-12-13]. https://pubmed.ncbi.nlm.nih.gov/38097102/. DOI: 10.1016/j.exer.2023.109750.
56. Liu Z, Xu J, Ma Q, et al. Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche[J/OL]. Sci Transl Med, 2020, 12(555): 1371[2020-08-05]. https://pubmed.ncbi.nlm.nih.gov/32759274/. DOI: 10.1126/scitranslmed.aay1371.
57.
58. Wong TY, Cheung CM, Larsen M, et al. Diabetic retinopathy[J/OL]. Nat Rev Dis Primers, 2016, 2: 16013[2016-03-17]. https://pubmed.ncbi.nlm.nih.gov/27159554/. DOI: 10.1038/nrdp.2016.12.
59. Nawaz IM, Rezzola S, Cancarini A, et al. Human vitreous in proliferative diabetic retinopathy: characterization and translational implications[J/OL]. Prog Retin Eye Res, 2019, 72: 100756[2019-04-02]. https://pubmed.ncbi.nlm.nih.gov/30951889/. DOI: 10.1016/j.preteyeres.2019.03.002.
60.
61.
62.
63.
64. Blasiak J, Hyttinen JMT, Szczepanska J, et al. Potential of long non-coding RNAs in age-related macular degeneration[J/OL]. Int J Mol Sci, 2021, 22(17): 9178[2021-08-25]. https://pubmed.ncbi.nlm.nih.gov/34502084/. DOI: 10.3390/ijms22179178.
65.
66. Brodzka S, Baszyński J, Rektor K, et al. The role of glutathione in age-related macular degeneration (AMD)[J/OL]. Int J Mol Sci, 2024, 25(8): 4158[2024-04-09]. https://pubmed.ncbi.nlm.nih.gov/38673745/. DOI: 10.3390/ijms25084158.
67.
68.
69.
70.
71. Emini Veseli B, Van Wielendaele P, Delibegovic M, et al. The PFKFB3 inhibitor AZ67 inhibits angiogenesis independently of glycolysis inhibition[J/OL]. Int J Mol Sci, 2021, 22(11): 5970[2021-05-31]. https://pubmed.ncbi.nlm.nih.gov/34073144/. DOI: 10.3390/ijms22115970.
72.
73. Galindo CM, Oliveira Ganzella FA, Klassen G, et al. Nuances of PFKFB3 signaling in breast cancer[J/OL]. Clin Breast Cancer, 2022, 22(4): e604-e614[2022-01-15]. https://pubmed.ncbi.nlm.nih.gov/35135735/. DOI: 10.1016/j.clbc.2022.01.002.
74. De Oliveira T, Goldhardt T, Edelmann M, et al. Effects of the novel PFKFB3 inhibitor KAN0438757 on colorectal cancer cells and its systemic toxicity evaluation In vivo[J/OL]. Cancers, 2021, 13(5): 1011[2021-02-28]. https://pubmed.ncbi.nlm.nih.gov/33671096/. DOI: 10.3390/cancers13051011.
75.
76. Xu J, Wang L, Yang Q, et al. Deficiency of myeloid PFKFB3 protects mice from lung edema and cardiac dysfunction in LPS-induced endotoxemia[J/OL]. Front Cardiovasc Med, 2021, 8: 745810[2021-09-29]. https://pubmed.ncbi.nlm.nih.gov/34660743/. DOI: 10.3389/fcvm.2021.745810.
77. Seo M, Kim JD, Neau D, et al. Structure-based development of small molecule PFKFB3 inhibitors: a framework for potential cancer therapeutic agents targeting the Warburg effect[J/OL]. PLoS One, 2011, 6(9): e24179[2011-09-21]. https://pubmed.ncbi.nlm.nih.gov/21957443/. DOI: 10.1371/journal.pone.0024179.
78. Abdali A, Baci D, Damiani I, et al. In vitro angiogenesis inhibition with selective compounds targeting the key glycolytic enzyme PFKFB3[J/OL]. Pharmacol Res, 2021, 168: 105592[2021-04-01]. https://pubmed.ncbi.nlm.nih.gov/33813027/. DOI: 10.1016/j.phrs.2021.105592.

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