Inhibition of Key Glycolytic Enzyme Hexokinase 2 Ameliorates Psoriasiform Inflammation in vitro and in vivo

Le Zhuang; Weiyuan Ma; Jing Jiao

doi:10.2147/CCID.S435624

Inhibition of Key Glycolytic Enzyme Hexokinase 2 Ameliorates Psoriasiform Inflammation in vitro and in vivo

Clin Cosmet Investig Dermatol. 2023 Nov 9:16:3229-3239. doi: 10.2147/CCID.S435624. eCollection 2023.

Authors

Le Zhuang¹, Weiyuan Ma², Jing Jiao¹

Affiliations

¹ Department of Dermatology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, People's Republic of China.
² Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China.

Abstract

Purpose: Epidermal keratinocytes with an abnormal glucose metabolism have been identified in psoriasis. Hexokinase 2 (HK2) is a crucial enzyme involved in glycolytic metabolic pathways. However, the expression of HK2 and its potential therapeutic effects in psoriasis remains unclear. This study aimed to investigate the expression pattern of HK2 and evaluate its therapeutic effects in psoriasis.

Patients and methods: A gene expression dataset (GSE121212) downloaded from the Gene Expression Omnibus (GEO) database was used to examine the expression of HK2 in psoriasis. HK2 RNA and protein expression were investigated in psoriasis vulgaris (n=5) and healthy (n=5) samples. Immunohistochemistry for HK2 was performed on psoriasis vulgaris (n=22) and healthy skin (n=10) samples. Additionally, HaCaT cells were treated with M5 (interleukin [IL]-17A, tumor necrosis factor-α, IL-1α, IL-22, and Oncostatin-M) to induce a psoriatic inflammation cell model. A mouse model of psoriatic inflammation was established using topical 5% imiquimod cream. Psoriasis-like cells and mouse models were treated with the HK2 inhibitor 3-bromopyruvate (3-BrPA). Cell proliferation, glucose consumption, and lactate production were assessed. Furthermore, the activation of nuclear factor-kappa B (NF-Kb) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) was investigated using Western blot analysis.

Results: According to the GEO dataset, HK2 expression was significantly elevated in psoriasis. Upregulation of HK2 in psoriatic tissues was confirmed by quantitative real-time polymerase chain reaction and Western blotting. The immunohistochemistry score for HK2 was higher in psoriatic lesions than in healthy skin. 3-BrPA inhibited the proliferation and glycolysis of M5-stimulated HaCaT cells. Topical 3-BrPA ameliorated imiquimod-induced psoriasis-like dermatitis. Activation of NF-kB and NLRP3 was downregulated by 3-BrPA treatment.

Conclusion: Our study revealed that the glycolytic enzyme HK2 was upregulated in psoriasis and that the HK2 inhibitor 3-BrPA exhibited therapeutic effects in psoriasis cell and mouse models.

Keywords: 3-bromopyruvate; glucose metabolism; glycolysis; proliferation; psoriasis.

Grants and funding

Research reported in this publication was supported by Shandong Province Natural Science Foundation (No. ZR2020QH138), the Doctoral Startup Fund of Affiliated Hospital of Weifang Medical University (No. 2021BKQ02), and the Traditional Chinese Medicine Science and Technology Project of Shandong Province (No. 2021Q093).