Application of anethomycin in preparation of medicine for treating hereditary hemochromia

Abstract

The invention discloses an application of anethomycin in preparation of a medicine for treating hereditary hemochromatosis. The anethomycin has the effect of promoting liver hepcidin expression, so that the liver iron level is reduced, and the anethomycin is used for treating hereditary hemosis. The research on the action mechanism of the anethomycin shows that the anethomycin promotes parenchymal hepatic cells to secrete hepcidin by up-regulating the expression of a key regulatory factor BMP6 of hepcidin expressed by hepatic sinus endothelial cells, so that the treatment application of hereditary hemochromia is realized, and the anethomycin has good commercial application prospects and scientific research values.

Description

Technical Field

[0001] The invention belongs to the field of drug therapy, and in particular relates to the application of anisomycin in preparing a drug for treating hereditary hemochromatosis. Background Art

[0002] Hereditary hemochromatosis is an autosomal recessive genetic disease. 90% of hereditary hemochromatosis is due to a point mutation in the HFE gene, which causes the 282nd cysteine ​​in its protein sequence to mutate to tyrosine (C282Y). Its pathological characteristics are excessive iron intake and iron deposition in tissues such as the liver, heart, and endocrine glands, leading to organ damage. The liver is the most commonly affected organ, usually accompanied by fatty liver and cirrhosis, and even leading to liver cancer. Therefore, the essence of hereditary hemochromatosis is an iron overload syndrome associated with an imbalance in iron homeostasis.

[0003] In the liver, hepcidin (HAMP), secreted by hepatocytes, plays a vital role in regulating the body's iron homeostasis. It binds to the pump ferritin on the cell membrane of duodenal epithelial cells and regulates the endocytosis and degradation of pump ferritin to precisely regulate the balance of iron homeostasis between absorption (small intestine), storage (hepatocytes and macrophages), and utilization (mostly for red bone marrow hematopoiesis). Low levels of hepcidin expression due to genetic defects are an important factor in the occurrence and development of hereditary hemochromatosis.

[0004] Hepcidin is regulated by bone morphogenetic protein 6 (BMP6) expressed by liver sinusoidal endothelial cells. Studies have found that when the iron content in liver cells increases, liver sinusoidal endothelial cells will express and secrete BMP6. After BMP6 binds to the BMP receptor on the membrane of liver parenchymal cells, it phosphorylates the intracellular Smad protein. The phosphorylated Smad1 / 5 / 8 binds to the Smad4 in the cytoplasm to form a complex and transfer and localize to the nucleus, thereby activating hepcidin transcription. The absence or inactivation mutation of hepcidin and BMP6 will lead to an imbalance in iron metabolism, thereby causing iron overload-related diseases, such as hemochromatosis.

[0005] Currently, the treatments for hereditary hemochromatosis are very limited, mainly including phlebotomy, oral or intravenous iron chelators, and treatment for complications. However, for patients with severe anemia, heart failure, and intolerance, intravenous phlebotomy is not feasible, and the iron chelators deferoxamine and deferiprone are being eliminated due to their high price, serious adverse reactions, and poor treatment compliance. Therefore, it is particularly important to find more effective drugs for the treatment of hereditary hemochromatosis. Summary of the invention

[0006] In view of the above problems existing in the prior art, the object of the present invention is to provide a new application of anisomycin in the preparation of drugs for treating hereditary hemochromatosis.

[0007] To achieve the above object, the technical solution adopted by the present invention includes:

[0008] The invention provides a new application of anisomycin in preparing a medicine for treating hereditary hemochromatosis.

[0009] The structure of anisomycin is shown in Formula I:

[0010]

[0011] Anisomycin, CAS No.: 22862-76-6, molecular weight: 265.30, chemical name is (2R, 3S, 4S)-2-[(4-methoxyphenyl)methyl]-3,4-pyrrolidinediol 3-acetate, which is a pyrrolidine antibiotic isolated from Streptomyces griseus. Anisomycin is an effective protein synthesis inhibitor that interferes with protein and DNA synthesis by inhibiting the peptidyl transferase 80 ribosome system. It is also a JNK activator that can enhance phosphorylated JNK. In clinical practice, anisomycin is used to treat diseases such as vaginitis caused by Trichomonas and dysentery caused by amoeba. In addition, it is also widely used to prevent and control fungal diseases of plants. The inventor unexpectedly discovered that anisomycin can stimulate hepatic sinusoidal endothelial cells to express BMP6, thereby promoting the secretion of hepcidin in the liver in vivo, and can reduce the liver iron load of mice with hereditary hemochromatosis, and is used to treat hereditary hemochromatosis.

[0012] Furthermore, the hereditary hemochromatosis is hereditary hemochromatosis associated with the HFE gene.

[0013] Furthermore, the drug treats hereditary hemochromatosis by:

[0014] 1) Upregulating the expression of BMP6 in the liver; and / or

[0015] 2) upregulating hepcidin expression in the liver; and / or

[0016] 3) Reduced iron absorption in the duodenum; and / or

[0017] 4) reduced serum iron levels and transferrin saturation; and / or

[0018] 5) Reduce liver iron levels; and / or

[0019] 6) Improve liver iron deposition.

[0020] Furthermore, the drug upregulates the expression of hepcidin by activating the BMP6 / SMAD1 / 5 signaling pathway.

[0021] Furthermore, the drug also includes pharmaceutically acceptable excipients.

[0022] Further, the dosage form of the drug is tablets, capsules, effervescent tablets, granules, powders, dispersible tablets, oral liquids, pills or injections. The above dosage forms can be prepared according to conventional methods in the prior art. In addition, the active ingredient of the drug of the present invention can be only anisomycin, or it can be a combination of anisomycin and other active ingredients.

[0023] Beneficial effects of the present invention:

[0024] The present invention discloses a new application of anisomycin in the preparation of a drug for treating hereditary hemochromatosis. Anisomycin has the effect of promoting the expression of hepcidin in the liver, thereby reducing serum iron levels and transferrin saturation, reducing liver iron levels, and improving liver iron deposition, and is used to treat hereditary hemochromatosis. The mechanism of action thereof is studied, and it is found that anisomycin activates the SMAD1 / 5 signaling pathway of hepatocytes by upregulating the expression of BMP6, a key regulatory factor of hepcidin expressed by hepatic sinusoidal endothelial cells, thereby promoting the secretion of hepcidin by hepatocytes, and realizing the therapeutic application of hereditary hemochromatosis, and has good commercial application prospects and scientific research value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The specific implementation modes of the present invention are further described in detail below in conjunction with the accompanying drawings.

[0026] Figure 1 A diagram showing that anisomycin activates Bmp6 and hepcidin expression in vivo and reduces iron levels; wherein,

[0027] A: 8-week-old C57BL / 6 male mice were intraperitoneally injected with 2 mg / kg anisomycin once. The mice were treated at 0, 2, 4, and 8 hours after the injection and liver tissues were obtained to extract RNA. Realtime-PCR was used to detect Bmp6 expression.

[0028] B: 8-week-old C57BL / 6 male mice were intraperitoneally injected with 2 mg / kg anisomycin once. The mice were treated at 0, 2, 4, and 8 hours after the injection and liver tissues were obtained to extract RNA. Realtime-PCR was used to detect Hamp expression.

[0029] C: 8-week-old C57BL / 6 male mice were intraperitoneally injected with 2 mg / kg anisomycin once. The mice were treated at 0, 2, 4, and 8 hours after the injection and liver tissues were obtained to extract RNA and detect IL-6 expression by Realtime-PCR.

[0030] D: 8-week-old C57BL / 6 male mice were intraperitoneally injected with 2 mg / kg anisomycin once, and serum iron levels were measured at 0, 2, 4, and 8 hours after injection;

[0031] E: 8-week-old C57BL / 6 male mice were intraperitoneally injected with 2 mg / kg anisomycin once, and the transferrin saturation was measured at 0, 2, 4, and 8 hours after injection;

[0032] F: 8-week-old C57BL / 6 male mice were intraperitoneally injected with 2 mg / kg anisomycin once. The mice were treated and liver tissues were obtained at 0, 2, 4 and 8 hours after injection. Western blotting was used to detect the phosphorylation level of SMAD1 / 5, a key protein in the BMP / SMAD pathway.

[0033] Figure 2 The figure shows that anisomycin activates hepcidin in the liver of Hfe knockout male mice and reduces liver iron deposition; wherein,

[0034] A: 8-week-old Hfe knockout C57BL / 6 male mice were intraperitoneally injected with 2 mg / kg anisomycin twice a week for 4 weeks. Liver RNA was extracted from treated mice and Hamp expression was detected by Realtime-PCR.

[0035] B: Immunohistochemical staining of liver pump ferritin in 8-week-old Hfe knockout C57BL / 6 male mice after intraperitoneal injection of 2 mg / kg anisomycin twice a week for 4 weeks;

[0036] C: Prussian blue staining of the duodenum of 8-week-old Hfe knockout C57BL / 6 male mice after intraperitoneal injection of 2 mg / kg anisomycin twice a week for 4 weeks;

[0037] D: Serum iron levels in 8-week-old Hfe knockout C57BL / 6 male mice after intraperitoneal injection of 2 mg / kg anisomycin twice a week for 4 weeks;

[0038] E: Liver iron content of 8-week-old Hfe knockout C57BL / 6 male mice after intraperitoneal injection of 2 mg / kg anisomycin twice a week for 4 weeks;

[0039] F: Prussian blue staining of the liver of 8-week-old Hfe knockout C57BL / 6 male mice after intraperitoneal injection of 2 mg / kg anisomycin twice a week for 4 weeks;

[0040] G: 8-week-old Hfe knockout C57BL / 6 male mice were treated with 2 mg / kg anisomycin intraperitoneally twice a week for 4 weeks, and liver tissues were obtained from the mice. Western blotting was used to detect the phosphorylation levels of SMAD1 / 5, a key protein in the BMP / SMAD pathway, and STAT3, a key protein in the IL6 / STAT3 pathway.

[0041] Figure 3A diagram showing that anisomycin activates SMAD1 / 5 phosphorylation and upregulates hepcidin expression in hepatic parenchymal cells in a paracrine manner by stimulating BMP6 expression in hepatic sinusoidal endothelial cells in vitro;

[0042] A: SK-Hep1 cells were treated with different concentrations of anisomycin for 6 hours, and the expression level of Bmp6 gene was detected by Realtime-PCR;

[0043] B: HepG2 cells were cultured for 2 hours using serum-free control medium, serum-free SK-Hep1 conditioned medium, and anisomycin-treated SK-Hep1 conditioned medium, and HepG2 cells were collected and HepG2 cell proteins were extracted. Western blotting was used to detect the phosphorylation levels of SMAD1 / 5, a key protein in the BMP / SMAD pathway, and STAT3, a key protein in the Il6 / STAT3 pathway.

[0044] C: HepG2 cells were cultured for 2 h using serum-free control medium, serum-free SK-Hep1 conditioned medium, and anisomycin-treated SK-Hep1 conditioned medium. HepG2 cells were collected, RNA was extracted, and Realtime-PCR was used to detect HAMP expression. DETAILED DESCRIPTION

[0045] In order to more clearly illustrate the present invention, the present invention is further described below in conjunction with preferred embodiments and drawings. It should be clear that the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] Embodiment 1:

[0047] 1 Test materials

[0048] 1.1 Experimental cells

[0049] Human hepatoma cell line HepG2 and human liver sinusoidal endothelial cell line SK-Hpe1 were purchased from the Cell Bank of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0050] 1.2 Experimental animals

[0051] 8-week-old SPF-grade C57BL / 6 mice (16, male) were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. 8-week-old Hfe knockout C57BL / 6 mice (16, male) were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. They were raised in an SPF-grade animal breeding environment.

[0052] 1.3 Primary Antibody

[0053] Rabbit anti-pSMAD1 / 5 (1:1000 dilution; ThermoFisher Scientific), rabbit anti-SMAD1 (1:1000 dilution; Cell Signaling Technology), rabbit anti-pSTAT3 (1:1000 dilution; Cell Signaling Technology), rabbit anti-STAT3 (1:1000 dilution; Cell Signaling Technology), rabbit anti-GAPDH (1:10000 dilution; Abcam), and rabbit anti-Vinculin (1:5000 dilution; ThermoFisher Scientific).

[0054] 2 Test methods

[0055] 2.1 Cell experiments

[0056] The experimental cells were cultured in MEM medium (Gibco) containing 10% fetal bovine serum (Gibco) at 37°C and 5% CO2 saturated humidity incubator. When the cells grew to 70-80% confluence, they were cultured for 6 hours in serum-free medium containing 0.01uM, 0.1uM, 1uM, 2uM, 5uM and 10uM anisomycin prepared with dimethyl sulfoxide (DMSO). The supernatant was discarded, the cells were rinsed with PBS 3 times, RNA was extracted by Trizol method, and the expression of BMP6 gene was detected by Realtime-PCR.

[0057] Human liver sinusoidal endothelial cell line SK-Hep1 cells and human liver cancer cell line HepG2 cells were used as experimental subjects. SK-Hep1 cells cultured in serum-free medium with dimethyl sulfoxide DMSO (1um) were used as blank control group, and SK-Hep1 cells cultured in serum-free medium with anisomycin (1um) were used as experimental group. The culture supernatant was collected after 24 hours of culture as conditioned medium. The conditioned medium was mixed with serum-free medium in a ratio of 1:1 and used as culture medium to culture HepG2 cells, and serum-free medium was used as control. HepG2 cells were collected after 2 hours of culture, HepG2 cell proteins were extracted, and the phosphorylation level of SMAD1 / 5 in HepG2 cells was detected. HepG2 cells were collected after 6 hours of culture, HepG2 cell RNA was extracted, cDNA was reverse transcribed, and Realtime-PCR was used to detect the expression level of hepcidin. Three replicate wells were set for each treatment, and the experiment was repeated three times.

[0058] 2.2 Animal experiments

[0059] Eight-week-old C57BL / 6 male mice were randomly divided into an experimental group and a control group. The control group was injected with solvent (corn oil), and the experimental group was injected with anisomycin (2 mg / kg) by intraperitoneal injection. 0 hours, 2 hours, 4 hours and 8 hours after injection. Intraperitoneal anesthesia was performed with a 5% chloral hydrate aqueous solution, blood was collected from the heart (serum was separated in time), and liver tissue was collected. Serum iron-related indicators, liver Bmp6 and hepcidin expression levels, and the expression and phosphorylation levels of key proteins in the liver hepcidin regulatory pathway were detected.

[0060] Eight-week-old Hfe knockout male C57BL / 6 mice were randomly divided into an experimental group and a control group. The control group was injected with solvent (corn oil), and the experimental group was injected with anisomycin (2 mg / kg). The mice were injected intraperitoneally twice a week for 4 consecutive weeks. Intraperitoneal anesthesia was performed with 5% chloral hydrate aqueous solution, and blood was collected from the heart (serum was separated in time), and liver and duodenal tissues were collected. Serum iron level, tissue iron level, hepcidin expression level in the liver, iron staining in the liver and duodenum, expression and phosphorylation level of key proteins in the hepcidin regulatory pathway in the liver, and localization of ferritin in the duodenal pump were detected.

[0061] 2.3 Protein extraction and western blotting

[0062] After lysing cells and tissues with RIPA lysis buffer (Merk) containing Protease Inhibitor Cocktail (Roche) and PhosSTOP (Roche), total protein was extracted. 30 μg of cell protein and 100 μg of liver tissue protein were transferred to PVDF membrane after 10% SDS-PAGE gel electrophoresis, and the membrane was incubated with specific antibodies (primary antibodies as described below) at 4°C overnight. Wash three times, incubate with peroxidase-labeled secondary antibodies (anti-rabbit IgG 1:5000, Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) at room temperature for 1 hour, and use a Western blotting color development kit (ECL system, Pierce, Thermo Scientific) for color development.

[0063] 2.4 RNA extraction and real-time PCR

[0064] RNA from cells and tissues was extracted using Trizol (ThermoFisher Scientific), and the specific operations were performed according to the instructions.

[0065] The RNA purity (OD260 / OD280≈1.9-2.1) and RNA concentration (ng / μl) were tested on Nanodrop 1000 Spectrophotometer, and the RNA concentration was adjusted to 1μg / μl. 1μg RNA was reverse transcribed using Transcriptor cDNA Synth.Kit (Roche). Realtime-PCR was performed in ThermoFisher Scientific 7500FAST, using FastStart TM General Green premix (Roche), the reaction system is 15μl, including SYBGREEN 7.5μL, cDNA 1μL, primer 2μl, ddH2O 4.5μL. Real-Time program is 95℃ pre-denaturation for 3 minutes, 40 cycles (95℃ 10 seconds per cycle, 60℃ 15 seconds during fluorescence detection), and melting curve detection. The primer sequences are as follows:

[0066] Mouse Gapdh:

[0067] Forward: 5'-TGGCCTTCCGTGTTCCTAC-3' (SEQ ID No: 1)

[0068] Reverse: 5'-GAGTTGCTGTTGAAGTCGCA-3' (SEQ ID No: 2)

[0069] Mouse Hamp:

[0070] Forward: 5'-AAGCAGGGCAGACATTGCGAT-3' (SEQ ID No: 3)

[0071] Reverse: 5'-CAGGATTGTGGCTCTAGGCTATGT-3' (SEQ ID No: 4)

[0072] Mouse Bmp6:

[0073] Forward: 5'-TCAACGACACCACAAAGAGTTC-3' (SEQ ID No: 5)

[0074] Reverse: 5'-TGCAAGACTTGGTAAATGCTGA-3' (SEQ ID No: 6)

[0075] Mouse IL-6:

[0076] Forward: 5'-TAGTCCTTCCTACCCCAATTTCC-3' (SEQ ID No: 7)

[0077] Reverse: 5'-TTGGTCCTTAGCCACTCCTTC-3' (SEQ ID No: 8)

[0078] Human GAPDH:

[0079] Forward: 5'-GAGTCAACGGATTTGGTCGT-3' (SEQ ID No: 9)

[0080] Reverse: 5'-GACAAGCTTCCCGTTCTCAG-3' (SEQ ID No: 10)

[0081] Human BMP6:

[0082] Forward: 5'-ACGCACACATGAATGCAACC-3' (SEQ ID No: 11)

[0083] Reverse: 5'-ACGGTTTGGGGACATACTCG-3' (SEQ ID No: 12)

[0084] PEOPLE HAMP:

[0085] Forward: 5'-TTTTCCCACAACAGACGGGA-3' (SEQ ID No: 13)

[0086] Reverse: 5'-CTCCTTCGCCTCTGGAACAT-3' (SEQ ID No: 14).

[0087] 2.5 Immunohistochemistry for ferritin

[0088] Mouse duodenum was fixed, embedded, and sliced, followed by dewaxing and antigen retrieval, and after removing endogenous peroxidase, fetal bovine serum was used for blocking. Then, the samples were incubated with a 1:200 dilution of pump ferritin antibody (Novus) at 4°C overnight. After washing three times with PBS, biotin-linked secondary antibodies were added and incubated for 1 hour at room temperature, and then DAB was used for color development.

[0089] 2.6 Serum iron, total iron binding capacity and tissue iron testing

[0090] Serum iron and total iron binding capacity assay kits (Ragen) were used to measure serum iron and transferrin saturation, and tissue iron was detected by colorimetric method.

[0091] 2.7 Tissue iron staining detection

[0092] Tissue iron staining was performed using Prussian blue staining.

[0093] 2.8 Statistical methods

[0094] The statistics were analyzed by Graphpad Prism8 software, and the experimental data were expressed as Mean ± SD. Tukey's test (ANOVA) was used for inter-group comparisons in cell and animal experiments, and Student's t-test was used for comparisons between two groups. * indicates that P < 0.05 is considered statistically significant.

[0095] 3 Test results

[0096] 3.1 Anisomycin can upregulate the expression of BMP6 and hepcidin in C57BL / 6 mice and reduce the iron level of mice.

[0097] The experiment found that anisomycin can upregulate the expression levels of Bmp6 and hepcidin in the liver of C57BL / 6 mice, but has no effect on the expression of IL-6 (see Figure 1 A, B, and C) and reduced serum iron levels and transferrin saturation in C57BL / 6 mice (see Figure 1 At the same time, anisomycin can activate the phosphorylation level of SMAD1 / 5 in the liver of C57BL / 6 mice (see Figure 1 Middle F). This indicates that anisomycin upregulates hepcidin expression mainly by activating the BMP6 / SMAD1 / 5 pathway in the liver of C57BL / 6 mice.

[0098] 3.2 Anisomycin can effectively improve liver iron deposition in Hfe knockout hemochromatosis mice

[0099] Hereditary hemochromatosis is a chronic iron overload disease, which is often caused by HFE gene mutation. Hfe knockout mice are a classic animal model of hemochromatosis. Their phenotype is similar to that of hemochromatosis patients with HFE gene mutation, showing abnormal decrease in hepcidin expression and systemic iron overload.

[0100] The experiment found that anisomycin can upregulate the expression level of hepcidin in the liver of Hfe knockout male C57BL / 6 mice (see Figure 2 Anisomycin can reduce the localization and protein amount of ferroportin on the cell membrane in the duodenum of Hfe knockout male C57BL / 6 mice (see Figure 2 B), and also increased iron retention in the duodenum of Hfe knockout male C57BL / 6 mice (see Figure 2 Anisomycin can downregulate serum iron levels in Hfe knockout male C57BL / 6 mice (see Figure 2Anisomycin can downregulate liver iron levels in Hfe knockout male C57BL / 6 mice (see Figure 2 Middle E). Anisomycin can improve liver iron accumulation in Hfe knockout male C57BL / 6 mice (see Figure 2 F). Anisomycin can upregulate the phosphorylation level of SMAD1 / 5 in the liver of Hfe knockout male C57BL / 6 mice, but has no effect on the IL-6 / STAT3 pathway (see Figure 2 Middle G). This indicates that anisomycin can upregulate hepcidin expression by activating the BMP6 / SMAD1 / 5 pathway in the liver of Hfe knockout male C57BL / 6 mice, reduce iron absorption in the duodenum, reduce serum iron and liver iron content, and improve liver iron deposition in hemochromatosis mice.

[0101] 3.3 Anisomycin stimulates BMP6 expression in hepatic sinusoidal endothelial cells, activates SMAD1 / 5 phosphorylation in hepatic parenchymal cells and upregulates hepcidin expression in a paracrine manner.

[0102] The experiment found that anisomycin can upregulate the expression level of BMP6 in SK-Hep1 cells, and the upregulation is correlated with the drug concentration (see Figure 3 (A).

[0103] Compared with HepG2 cells cultured in serum-free medium, the phosphorylation level of SMAD1 / 5 in HepG2 cells cultured with SK-Hep1 culture supernatant was significantly increased, but the supernatant of SK-Hep cells cultured with anisomycin further increased the phosphorylation level of SMAD1 / 5 in HepG2 cells (see Figure 3 Middle B) shows that anisomycin can activate SMAD1 / 5 phosphorylation in hepatic parenchymal cells in a paracrine manner by stimulating BMP6 expression in hepatic sinusoidal endothelial cells.

[0104] Compared with HepG2 cells cultured in serum-free medium, the expression of hepcidin in HepG2 cells cultured with SK-Hep1 culture supernatant was significantly increased, but the supernatant of SK-Hep cells cultured with anisomycin further increased the expression level of hepcidin in HepG2 cells (see Figure 3 Middle C) indicates that anisomycin can stimulate the expression of BMP6 in hepatic sinusoidal endothelial cells, thereby activating hepcidin expression in hepatic parenchymal cells in a paracrine manner.

[0105] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not limitations on the implementation methods of the present invention. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the implementation methods here. All obvious changes or modifications derived from the technical solution of the present invention are still within the protection scope of the present invention.

Claims

1. Use of anisomycin in the preparation of a drug for treating hereditary hemochromatosis, characterized in that: The structure of anisomycin is shown in Formula I:

2. The use according to claim 1, characterized in that: The hereditary hemochromatosis is hereditary hemochromatosis associated with the HFE gene.

3. The use according to claim 1, characterized in that: The drug treats hereditary hemochromatosis by: 1) Upregulating the expression of BMP6 in the liver; and / or 2) upregulating hepcidin expression in the liver; and / or 3) Reduced iron absorption in the duodenum; and / or 4) reduced serum iron levels and transferrin saturation; and / or 5) Reduce liver iron levels; and / or 6) Improve liver iron deposition.

4. The use according to claim 3, characterized in that: It upregulates the expression of hepcidin by activating the BMP6 / SMAD1 / 5 signaling pathway.

5. The use according to claim 1, characterized in that: The drug also includes pharmaceutically acceptable excipients.

6. The use according to claim 1, characterized in that: The dosage form of the drug is tablet, capsule, effervescent tablet, granule, powder, dispersible tablet, oral solution, pill or injection.

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