Application of UPP1 inhibitors in the preparation of drugs for treating psoriasis

Abstract

The present invention relates to the use of UPP1 inhibitors in the preparation of drugs for treating psoriasis, and belongs to the field of biomedicine technology. The present invention uses imiquimod to induce the formation of a psoriasis animal model, and administers the UPP1 inhibitor 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate potassium (CPBMF65) by oral gavage, and then detects its therapeutic effect on psoriasis. The results show that oral gavage of CPBMF65 can significantly alleviate psoriasis symptoms. The present invention discloses for the first time the role of uridine phosphorylase-1 in promoting the cell viability and cell cycle progression of HaCaT cells through the glycolysis pathway in the pathogenesis of psoriasis, providing a new drug source for the treatment of psoriasis while opening up a new application field for the application of CPBMF65.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular, relates to the use of a UPP1 inhibitor in the preparation of a medicament for treating psoriasis. Background Art

[0002] Psoriasis is a chronic inflammatory systemic disease characterized by recurrent erythematous rashes covered by clear scales, affecting over 60 million adults and children worldwide. It is easily associated with a variety of metabolic or cardiovascular diseases. The main pathological changes in psoriasis are abnormal proliferation of epidermal keratinocytes, marked vasodilation, and prominent inflammatory cell infiltration around dermal capillaries. Currently, a variety of treatments, including systemic treatment, topical medications, and phototherapy, can alleviate psoriatic lesions by inhibiting excessive keratinocyte proliferation and / or regulating keratinocyte differentiation. Intervention of these cellular events is crucial for the treatment of psoriasis. However, the underlying mechanisms involved need to be clarified.

[0003] Numerous studies have demonstrated that IL-17 and TNF are two important inflammatory cytokines implicated in the pathogenesis of psoriasis. Interleukin (IL)-6 is also a key component of the cytokine network involved in the pathogenesis of psoriasis. IL-6 is expressed at elevated levels in both messenger RNA (mRNA) and protein in psoriasis, and its pleiotropic effects include stimulating epidermal keratinocyte proliferation and promoting the differentiation of IL-17-producing T lymphocytes. Crosstalk exists between IL-17 and TNF and IL-6. The primary targets of IL-17 in psoriasis include keratinocytes, endothelial cells, and innate immune cells. In keratinocytes, IL-17 stimulates the production of inflammatory cytokines, including IL-1β, TNF-α, and IL-6. As an active stimulator of cell survival and proliferation, signal transducer and activator of transcription 3 (STAT3) is considered an essential effector for activation of the IL-6 / Janus kinase (JAK) pathway. Activated STAT3 plays a crucial role in the development and pathogenesis of psoriatic inflammation. In short, we hypothesized that in psoriasis, IL-17 stimulates keratinocytes to produce IL-6, which in turn promotes keratinocyte proliferation via an autocrine pathway.

[0004] Glycolysis can provide exceptionally rapid energy and a greater abundance of metabolic intermediates for biosynthesis during cell proliferation. The detailed metabolic processes of glycolysis in cancer cells have been elucidated. Even under conditions of ample oxygen supply, aerobic glycolysis can enhance glucose uptake and ultimately convert pyruvate into lactate. This, known as the "Warburg effect," is implicated in a series of key entry points in tumorigenesis, growth, invasion, and migration during cancer development. Therefore, targeting anti-glycolytic pathways has been shown to be a promising new cancer treatment option. It is widely believed that psoriatic skin is associated with excessive keratinocyte proliferation and abnormal T lymphocyte activation. Accumulating evidence suggests that glycolysis is involved in the pathogenesis of psoriasis, through Th17 / Th1 cell differentiation and keratinocyte proliferation. This further suggests that the glycolytic pathway is involved in the pathogenesis of psoriasis.

[0005] Human uridine phosphorylase-1 (UPP1) is a key enzyme in the pyrimidine salvage pathway and is crucial for regulating uridine homeostasis. Furthermore, UPP1 catalyzes the reversible phosphorylation of uridine nucleoside to uracil, thereby increasing uracil levels in various pathophysiological processes, such as RNA synthesis. Currently, UPP1 is primarily studied in the fields of cancer and oncology. Upregulation of UPP1 leads to increased thyroid tumor volume, while downregulation of UPP1 inhibits the proliferation of thyroid cancer cell lines. Similar results were observed in HepG2 cell proliferation after treatment with a synthetic human UPP1 inhibitor. Regarding the precise mechanisms of psoriasis, the interplay between keratinocytes and immune cells is central to the disease. Multiple cytokine stimulation may contribute to the rapid proliferation of keratinocytes, with high levels of proinflammatory cytokines or amplified inflammation acting as a feedback loop in response to growing keratinocytes. Further studies are needed to determine whether UPP1 enhances keratinocyte proliferation and promotes the development of psoriasis.

[0006] The present invention has conducted a large number of experimental studies, and the results show that UPP1 promotes the cell viability and cell cycle progression of human keratinocytes HaCaT cells by regulating the glycolysis pathway, thereby promoting the development of psoriasis. Therefore, the present invention uses imiquimod to induce the formation of a psoriasis animal model, and administers the UPP1 inhibitor 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-ol potassium (CPBMF65) by gavage, and then detects its therapeutic effect on psoriasis. The experimental results show that gavage of CPBMF65 can significantly alleviate the symptoms of psoriasis, which further illustrates that UPP1 is involved in the pathogenesis of psoriasis. CPBMF65 is a known UPP1 inhibitor, but there has been no report on its use in the treatment of psoriasis. Summary of the Invention

[0007] The present invention aims to provide the use of a UPP1 inhibitor in the preparation of a medicament for treating psoriasis. The present invention uses imiquimod to induce a psoriasis animal model, and administers the UPP1 inhibitor potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65) by oral gavage. The therapeutic effect on psoriasis is then tested. The results show that oral gavage of CPBMF65 can significantly alleviate psoriasis symptoms.

[0008] The technical problem to be solved by this invention is that glycolysis is crucial for the excessive proliferation of keratinocytes in psoriasis, and uridine phosphorylase-1 (UPP1) functions as a promoter of cancer cell proliferation. However, little is known about whether UPP1 promotes keratinocyte proliferation and accelerates the progression of psoriasis. Furthermore, there are no reports on the use of the known UPP1 inhibitor CPBMF65 in the treatment of psoriasis.

[0009] The purpose of the present invention can be achieved through the following technical solutions:

[0010] The present invention discloses the use of a UPP1 inhibitor in preparing a medicine for treating psoriasis.

[0011] Furthermore, psoriasis is psoriasis vulgaris, erythrodermic psoriasis, arthritic psoriasis or pustular psoriasis.

[0012] Furthermore, the UPP1 inhibitor is potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridin-2-olate (CPBMF65).

[0013] Furthermore, the drug is a drug prepared with a UPP1 inhibitor as an active ingredient.

[0014] Furthermore, the medicine also contains a pharmaceutically acceptable carrier.

[0015] Furthermore, the dosage form of the drug is an oral dosage form or an external dosage form.

[0016] Furthermore, the oral dosage form is capsule, tablet, granule or oral solution.

[0017] Furthermore, the external dosage form is an ointment, cream, gel, aerosol, spray or lotion.

[0018] The present inventors conducted extensive experimental studies, and the results showed that UPP1 promotes cell viability and cell cycle progression in human keratinocytes, HaCaT cells, by regulating the glycolytic pathway. The present inventors first used bioinformatics to analyze UPP1 gene expression and its associated reactome. The results showed that UPP1 mRNA expression, cell cycle progression, the IL-6 / JAK / STAT3 pathway, and glycolysis were positively correlated with psoriasis. Next, cell proliferation, cell cycle, and glycolysis were measured after UPP1 silencing or overexpression. The results showed that UPP1 overexpression increased cell proliferation, cell cycle progression, and glycolysis, which was the opposite of UPP1 silencing. Importantly, STAT3 inhibitors reduced UPP1 expression because STAT3 can bind to the UPP1 promoter. In summary, UPP1 is significantly activated by the IL-6 / STAT3 pathway and can regulate glycolysis to regulate cell proliferation and cell cycle progression in keratinocytes during the development of psoriasis.

[0019] This study discovered the role of uridine phosphorylase-1 in the pathogenesis of psoriasis by promoting cell viability and cell cycle progression of HaCaT cells through the glycolysis pathway. Imiquimod was used to induce an animal model of psoriasis and to identify the UPP1 inhibitor CPBMF65 for the treatment of psoriasis. Experimental results showed that CPBMF65 could significantly alleviate psoriasis symptoms, further demonstrating that UPP1 is involved in the pathogenesis of psoriasis.

[0020] Beneficial effects of the present invention:

[0021] (1) The technical solution of the present invention discloses for the first time the role of uridine phosphorylase-1 in promoting the cell viability and cell cycle progression of HaCaT cells through the glycolysis pathway in the pathogenesis of psoriasis, which provides assistance for finding effective treatment methods or developing effective drugs.

[0022] (2) In the technical solution of the present invention, by discovering the role of uridine phosphorylase-1 in promoting the cell viability and cell cycle progression of HaCaT cells through the glycolysis pathway in the pathogenesis of psoriasis, a drug that can significantly alleviate psoriasis was found, and then the new medicinal value of the known UPP1 inhibitor CPBMF65 was discovered, opening up a new application field for the application of CPBMF65. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 :UPP1 and its related pathways are involved in the pathogenesis of psoriasis; among them, Figure 1 A is the expression of UPP1 mRNA in psoriatic and normal samples, NN = normal skin in control group, PN = uninvolved skin in case, PP = psoriatic skin involved in case; Figure 1BD are GSEA results. ***P < 0.001 compared with NN, ###P < 0.001.

[0024] Figure 2 :UPP1 silencing inhibited IL-6-induced HaCaT cell viability increase and cell cycle progression; Figure 2 AC shows the expression of UPP1 in HaCaT cells treated with 10 ng / mL hrIL-6 for 0, 6, 12, 24, and 48 hours; Figure 2 D is the cell viability of each group detected by CCK-8 assay at 0, 6, 12, 24, and 48 h; Figure 2 EF is the cell cycle of each group measured by flow cytometry, Figure 2 The bars in each group in histogram (E) are, from left to right, Control, IL-6, IL-6+shNC, IL-6+shUPP1-1, and IL-6+shUPP1-2. In the figure, Control, IL-6, and IL-6+shNC represent blank control HaCaT cells, HaCaT cells treated with IL-6, and HaCaT cells treated with IL-6 and infected with NC lentivirus, respectively. IL-6+shUPP1-1 and IL-6+shUPP1-2 represent IL-6-treated HaCaT cells with UPP1 silenced. **P<0.01, ***P<0.001 compared with 0 h or the control group, #P<0.05 compared with IL-6+shNC.

[0025] Figure 3 :UPP1 silencing inhibits IL-6-induced glycolytic activity in HaCaT cells; Figure 3 AC are the ECAR evaluation results of each group; Figure 3 D is the change of ATP level in each group; Figure 3 EF is the expression of UPP1, PKM2 and LDHA in each group, Figure 3 The bars in the histogram (F) represent, from left to right, Control, IL-6, IL-6+shNC, IL-6+shUPP1-1, and IL-6+shUPP1-2. In the figure, Control, IL-6, and IL-6+shNC represent untreated HaCaT cells, IL-6-treated HaCaT cells, and IL-6+shNC-treated HaCaT cells infected with NC lentivirus, respectively. IL-6+shUPP1-1 and IL-6+shUPP1-2 represent IL-6-treated HaCaT cells with UPP1 silenced. **P<0.01, ***P<0.001 compared with the control group, ##P<0.01 compared with IL-6+shNC.

[0026] Figure 4: 2-DG-inhibited UPP1 overexpression induced increased cell viability, cell cycle progression, and glycolytic activity in HaCaT cells; Figure 4 A is the cell viability of each group; Figure 4 BC is the cell cycle progression of each group; Figure 4 DF are the ECAR evaluation results of each group; Figure 4 G is the change of ATP level in each group; Figure 4 HI represents the expression of UPP1, PKM2, and LDHA in each group. Vector, oeUPP1, and oeUPP1+2-DG represent HaCaT cells infected with a blank lentivirus, HaCaT cells infected with the oeUPP1 lentivirus, and HaCaT cells infected with the oeUPP1 lentivirus and treated with 2-DG, respectively. ***P < 0.001 compared with vector, ###P < 0.001 compared with oeUPP1.

[0027] Figure 5 : IL-6 increases the expression of UPP1 in HaCaT cells by activating the STAT3 pathway; Figure 5 AC, expression of UPP1 was measured using RT-qPCR and Western blotting; Figure 5 D is the binding site between STAT3 and UPP1 promoter predicted using the JASPAR database; Figure 5 E shows the binding between STAT3 and the UPP1 promoter assessed using a dual-luciferase assay. Control, IL-6, and IL-6+Static represent blank control HaCaT cells, HaCaT cells treated with IL-6, and HaCaT cells treated with IL-6 and Static, respectively. ***P < 0.001 compared with the control group; ###P < 0.001 compared with IL-6.

[0028] Figure 6 :2-DG inhibits the cell viability and cell cycle progression of HaCaT cells induced by IL-6; Figure 6 A is the cell viability of HaCaT cells in each group at 0, 12, 24, and 48 hours; Figure 6 BC represents the cell cycle progression in each group. In the figure, Control, IL-6, and IL-6+2-DG represent blank control HaCaT cells, HaCaT cells treated with IL-6, and HaCaT cells treated with IL-6 and 2-DG, respectively. ***P < 0.001 compared with the control group, ###P < 0.001 compared with IL-6. DETAILED DESCRIPTION

[0029] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0030] Example 1:

[0031] 1. Use bioinformatics methods to analyze the correlation between UPP1 expression and psoriasis

[0032] Bioinformatics analysis of the GEO database (GSE13355 series) showed that the expression of UPP1 mRNA in psoriasis samples was significantly higher than that in normal samples ( Figure 1 A). In addition, GSEA results showed that the IL-6 / STAT3 pathway, cell cycle progression, and glycolysis were positively correlated with UPP1 expression ( Figure 1 BD). These results suggest that UPP1 and its related pathways are involved in the pathogenesis of psoriasis.

[0033] 2. Verify the effect of UPP1 silencing on IL-6-induced HaCaT cell viability and cell cycle progression

[0034] To analyze the potential correlation between IL-6 and UPP1, human immortalized keratinocytes (HaCaT) were selected and treated with IL-6. Figure 2 As shown in AC, IL-6 treatment significantly increased UPP1 mRNA or protein levels in a dose-dependent manner. Bioinformatics analysis predicted that UPP1 may affect the cell cycle progression of HaCaT cells. CCK8 assay, flow cytometry, and lentiviral transfection were also performed to precisely investigate the effect of UPP1 on cell proliferation. Figure 2 As shown in D, IL-6 effectively enhanced the viability of HaCaT cells, while silencing UPP1 reduced IL-6-induced HaCaT proliferation. In terms of cell cycle progression, IL-6 significantly improved cell proliferation, especially in the G1-S phase, which is the key commitment for cell division and DNA replication ( Figure 2 E and F). These results indicate that IL-6 promotes cell viability and cell cycle progression through UPP1.

[0035] 3. Verify the effect of UPP1 silencing on glycolytic activity of HaCaT cells induced by IL-6

[0036] Glucose is the basic energy unit in tissues, and cell activity itself requires a large amount of ATP accompanied by oxygen consumption. Pyruvate kinase (PK) is one of the key enzymes of glycolysis and can be divided into four different subtypes, including L, R, M1 and M2, of which PKM2 tetramer mainly manipulates the glycolysis process. LDHA converts the main part of glucose storage into lactate, despite the availability of oxygen, converting the use of glucose from simple energy production to enhancing cell proliferation. In the present invention, the effect of UPP1 on glycolysis was identified under the induction of IL-6. By evaluating ECAR, it was shown that the glycolytic flux and glycolytic capacity of HaCaT cells were upregulated after IL-6 stimulation, while silencing UPP1 made it ineffective ( Figure 3 AC). Figure 3 D shows the changes in ATP levels in each group. In detail, IL-6-induced glycolysis led to an increase in ATP levels, and this trend was blocked when UPP1 was silenced. Western blotting was performed to test the expression of glycolysis-related proteins such as PKM2 and LDHA. Similar results were obtained when IL-6 induced glycolysis through UPP1, which was neutralized by UPP1 silencing ( Figure 3 E and F). These results indicate that UPP1 silencing inhibits active glycolysis in IL-6-stimulated HaCaT cells.

[0037] 4. Further elucidation of the relationship between UPP1 and glycolysis through 2-DG treatment

[0038] To further elucidate the relationship between UPP1 and glycolysis, HaCaT cells were infected with oeUPP1 lentivirus and then treated with 25M2-DG (a glycolysis inhibitor). Figure 4 As shown in Figure A, after oeUPP1 treatment, HaCaT cell proliferation increased dramatically, which was abolished by further 2-DG treatment. In terms of cell cycle progression, oeUPP1 infection accelerated the transition of more HaCaT cells to the S phase to undergo mitosis, while HaCaT cells treated with 2-DG were mainly arrested in the G0-G1 phase compared with control HaCaT cells ( Figure 4 B and C). In addition, the potential effect of 2-DG on glycolysis was also evaluated in oeUPP1-treated HaCaT cells. The ECAR in HaCaT cells was significantly enhanced in response to oeUPP1, while 2-DG treatment effectively reversed this trend ( Figure 4 DF). Simultaneous trends in ATP, PKM2, and LDHA levels were found, with oeUPP1 treatment leading to a significant enhancement of glycolytic activity, whereas further 2-DG treatment negated this effect ( Figure 4 GI). In conclusion, oeUPP1 promoted cell viability, cell cycle progression, and glycolysis, which were counteracted by the glycolysis inhibitor 2-DG.

[0039] 5. IL-6 increases the expression of UPP1 in HaCaT cells by activating the STAT3 pathway

[0040] Based on the above conclusions, UPP1 plays a crucial role in glycolysis during the development of psoriasis and is activated by IL-6. To clarify the upstream-downstream sequence between UPP1 and STAT3, HaCaT cells were treated with 5MStattic. The results showed that UPP1 mRNA and protein levels were decreased ( Figure 5 AC). The precise correlation between UPP1 and STAT3 was assessed by dual-luciferase assay. Figure 5 As shown in D and E, STAT3 binds to the UPP1 promoter. These results indicate that IL-6 promotes UPP1 expression through activation of STAT3.

[0041] 6. 2-DG inhibits IL-6-induced cell viability and cell cycle progression of HaCaT cells

[0042] To further ensure the positive effect of IL-6 on cell viability via glycolysis in HaCaT cells, the related inhibitor 2-DG was used. Figure 6 As shown in Figure A, IL-6 can effectively enhance the viability of HaCaT cells, and this effect is inhibited by 2-DG. Similar results were also demonstrated for cell cycle progression ( Figure 6 B and C). These results indicate that IL-6 promotes cell viability and cell cycle progression through glycolysis.

[0043] Example 2

[0044] Effect of CPBMF65 of the present invention on mouse psoriasis model

[0045] 1. Main experimental materials

[0046] Animals: SPF-grade BALB / c female mice, weighing 148-173 g, were purchased from Liaoning Changsheng Biotechnology Co., Ltd.

[0047] Main drugs and reagents: CPBMF65 (the synthesis method has been disclosed in the document "Design of Novel Potent Inhibitors of Human Uridine Phosphorylase-1: Synthesis, Inhibition Studies, Thermodynamics, and in Vitro Influence on 5-Fluorouracil Cytotoxicity" (Daiana Renck, Pablo Machado, Andre A. Souto, Leonardo A. Rosado, Thais Erig, Maria M. Campos, Caroline B. Farias, Rafael Roesler, Luis FSM Timmers, Osmar N. de Souza, Diogenes S. Santos, Luiz A. Basso. [J]. Journal of Medicinal Chemistry, 2013)), imiquimod cream (purchased from Sichuan Mingxin Pharmaceutical Co., Ltd.), and methotrexate (purchased from Shanghai SPH Xinyi Pharmaceutical Factory Co., Ltd.).

[0048] 2. Experimental methods

[0049] Female BALB / c mice were randomly divided into four groups, with six mice in each group. They were housed at room temperature and, after acclimation, anesthetized with an intraperitoneal injection of sodium pentobarbital (79 mg / kg). Hair was removed from an approximately 3×3 cm area on the back of the mice. Imiquimod ointment (68.0 mg) was applied daily to the exposed area of ​​the mice's backs. Mice in the control group were treated with petrolatum ointment (68.0 mg) daily for 10 consecutive days. The drugs were administered according to the following grouping and dosage:

[0050] (1) Blank group: normal saline, gavage

[0051] (2) Model group: normal saline, gavage

[0052] (3) Methotrexate group: 1 mg / kg, oral administration, based on the clinical dosage for patients weighing 70 kg

[0053] (4) CPBMF65 group: 9 mg / kg, oral administration, based on the clinical dose for patients weighing 70 kg

[0054] The Psoriasis Area and Severity Index (PASI) was used to score the skin lesions on the back of the mice. It includes three major indicators: erythema, scaling, and infiltration (each indicator has a score of 0-4 points), and the sum of the three is the total score, which is the comprehensive PASI score. 0 points: none; 1 point: mild; 2 points: moderate; 3 points: severe; 4 points: extremely severe. The skin was then removed from the back of the mouse, fixed with 4% paraformaldehyde solution, and embedded in paraffin. Paraffin-embedded (5-10 μm) sections were prepared and stained with HE, and examined under an optical microscope. At the same time, 5 representative sites on the section were selected, and their thickness was measured. The average value of the 5 sites was taken as the epidermal thickness. The experimental results are shown in Table 1-2.

[0055] 3. Experimental results

[0056] 3.1 Psoriasis Area and Severity Index (PASI)

[0057] Table 1

[0058] project PASI total score Blank group 0 Model Group 7.48±1.15 Methotrexate group 0.81±0.73 CPBMF65 group 1.26±1.01

[0059] As can be seen from the data in Table 1, the PASI score of the psoriasis skin of mice was significantly reduced after 10 days of oral gavage treatment with CPBMF65, indicating that CPBMF65 can significantly improve the skin inflammatory response of imiquimod-induced psoriasis mouse model animals, reduce the degree of skin lesions, and alleviate skin symptoms such as erythema, scaling, and infiltration. Its effect is close to that of the positive control drug methotrexate.

[0060] 3.2 Pathological changes of skin lesions and epidermal thickness

[0061] Table 2

[0062] project Epidermal thickness (μm) Blank group 29.74±2.19 Model Group 113.24±1.83 Methotrexate group 52.06±4.25 CPBMF65 group 56.33±3.98

[0063] Microscopic observation revealed that the epidermis of mice in the blank group was thin, while the model group showed a significant increase in epidermal thickness, with marked hyperkeratosis accompanied by parakeratosis, and significant vascular proliferation and expansion, exhibiting typical psoriasis-like symptoms. As shown in Table 2, compared with the model group, the epidermal thickness of mice in the methotrexate and CPBMF65 groups was significantly reduced, indicating that CPBMF65 can significantly reduce the thickness of skin lesions in mice.

[0064] The above results confirm that CPBMF65 can effectively treat psoriasis, opening up a new application field for CPBMF65, and no obvious adverse reactions were shown during animal experiments.

[0065] Throughout the specification, references to terms such as "one embodiment," "example," or "specific example" indicate that the specific features, structures, materials, or characteristics described in conjunction with that embodiment or example are included in at least one embodiment or example of the present invention. In this specification, schematic representations of these terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0066] The above contents are merely examples and explanations of the present invention. Those skilled in the art may make various modifications or additions to the described specific embodiments or replace them in similar ways. As long as they do not deviate from the invention or exceed the scope defined by the claims, they should all fall within the scope of protection of the present invention.

Claims

1. Use of a UPP1 inhibitor in the preparation of a medicament for treating psoriasis, characterized in that: The UPP1 inhibitor is potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate.

2. Use of the UPP1 inhibitor according to claim 1 in the preparation of a medicament for treating psoriasis, characterized in that: The medicine is a medicine prepared with UPP1 inhibitor as an effective ingredient.

3. Use of the UPP1 inhibitor according to claim 1 in the preparation of a medicament for treating psoriasis, characterized in that: The medicine also contains a pharmaceutically acceptable carrier.

4. Use of the UPP1 inhibitor according to claim 1 in the preparation of a medicament for treating psoriasis, characterized in that: The dosage form of the medicine is an oral dosage form or an external dosage form.

5. Use of the UPP1 inhibitor according to claim 1 in the preparation of a medicament for treating psoriasis, characterized in that: The oral dosage form is a capsule, tablet, granule or oral liquid; the external dosage form is an ointment, cream, gel, aerosol, spray or lotion.

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