Application of OGG1 micromolecule agonist in preparation of medicine for treating liver inflammatory diseases

Abstract

The invention relates to the field of biological medicines, and discloses application of an OGG1 micromolecule agonist in preparation of a medicine for treating liver inflammatory diseases. According to the micromolecule TH10785, by activating the beta, delta-lyase activity of DNA repair enzyme OGG1, the oxidized DNA repair capacity is remarkably enhanced, ROS accumulation in liver cells is reduced, NF-kappa B signal channel activation and proinflammatory factor release are inhibited, and therefore liver inflammation and fibrosis are effectively relieved. Meanwhile, the medicine can inhibit the activation of B cells and the formation of plasma cells, finally reduces the generation of autoimmune antibodies, and improves the immune imbalance state of autoimmune hepatitis. The invention provides an innovative treatment strategy based on OGG1 enzyme function amplification, and a new pharmacological approach is provided for treatment of chronic liver diseases and immunological liver injury.

Description

Technical Field

[0001] This application relates to the field of biomedicine, and more specifically, to the use of OGG1 small molecule agonists in the preparation of medicaments for the treatment of inflammatory liver diseases. Background Technology

[0002] Metabolic-associated steatohepatitis (MAS) and cholestatic liver disease are chronic liver diseases characterized by hepatocyte lipid metabolism disorders, oxidative stress, and inflammatory responses, which can eventually lead to liver fibrosis, cirrhosis, and even liver cancer. In recent years, the incidence of immune-mediated liver diseases such as autoimmune hepatitis (AIH) has also been gradually increasing. Their common feature is persistent hepatocyte damage caused by chronic inflammation and immune abnormalities.

[0003] Current treatment strategies mainly focus on metabolic regulation (such as PPARα / δ agonists and thyroid hormone receptor β modulators), anti-inflammatory drugs (such as corticosteroids, UDCA, OCA, etc.), and anti-fibrotic drugs. However, these drugs are mostly indirect regulators and cannot effectively restore the oxidative damage repair capacity of hepatocytes. Furthermore, long-term use can easily lead to metabolic side effects or immunosuppression.

[0004] In recent years, the DNA repair enzyme OGG1 (8-oxoguanine DNA glycosylase 1) has been considered to play a crucial role in maintaining hepatocyte oxidative homeostasis, and its deficiency is closely related to the progression of MASH and cholestatic liver disease. Some small-molecule inhibitors or agonists of OGG1 have been reported, but their activation mechanism is mainly limited to increasing the activity of glycosylases, and they have not yet been able to endow it with new catalytic functions, nor have they shown significant therapeutic effects in inflammatory liver disease models. Summary of the Invention

[0005] Existing treatments have the following limitations: (1) Indirect target and single mechanism of action. Existing drugs mostly target metabolic pathways or inflammatory factors, making it difficult to fundamentally repair hepatocyte DNA damage and oxidative stress; (2) Limited efficacy and easy relapse. Most anti-inflammatory drugs can only temporarily suppress the immune response, and it is easy to relapse after drug withdrawal; (3) Lack of catalytic drug mechanism. There are currently no drugs that activate endogenous repair enzymes through small molecules and endow them with new catalytic activity; (4) Insufficient effect on immune-related liver diseases. In autoimmune hepatitis, excessive activation of B cells plays a key role in the pathological process, but existing drugs have limited effect on regulating B cell activity.

[0006] Therefore, there is an urgent need for a novel drug that can repair oxidative damage by catalytically activating endogenous enzymes, while simultaneously inhibiting liver inflammation and abnormal B cell activation, in order to achieve effective treatment for MASH, cholestatic liver disease, and autoimmune hepatitis.

[0007] The purpose of this invention is to provide a novel use of a small molecule OGG1 activator (TH10785) in the preparation of drugs for treating inflammatory liver diseases. This small molecule significantly enhances oxidative DNA repair capacity, reduces ROS accumulation in hepatocytes, and inhibits NF-κB signaling pathway activation and pro-inflammatory factor release by activating the β and δ-lysin activity of the DNA repair enzyme OGG1, thereby effectively alleviating liver inflammation and fibrosis. Simultaneously, this drug can inhibit B cell activation and plasma cell formation, ultimately reducing the production of autoimmune antibodies and improving the immune imbalance in autoimmune hepatitis. This invention proposes an innovative therapeutic strategy based on OGG1 enzyme function amplification, providing a new pharmacological approach for the treatment of chronic liver disease and immune-mediated liver injury.

[0008] This application provides the use of OGG1 small molecule agonists in the preparation of medicaments for the treatment of inflammatory liver diseases. Furthermore, the OGG1 small molecule agonist is TH10785.

[0009] Furthermore, the inflammatory liver diseases include metabolic-associated steatohepatitis, cholestatic liver disease, and autoimmune hepatitis.

[0010] In summary, this application has the following beneficial effects: 1. Clear therapeutic use: This invention clearly defines the use of this small molecule in the treatment of MASH, cholestatic liver disease and autoimmune hepatitis, achieving intervention targeting the specific pathological mechanisms of liver diseases.

[0011] 2. Reduce liver damage and fibrosis: By improving oxidative DNA damage and inhibiting local inflammatory responses in the liver, this invention can effectively reduce hepatocellular damage, inflammatory infiltration, and the progression of liver fibrosis.

[0012] 3. Regulation of immune response: The drug of this invention can inhibit excessive activation of B cells and reduce the infiltration of M1 macrophages, thereby regulating the immune environment and alleviating immune-mediated liver damage.

[0013] 4. Controllable dosage and good safety: At effective doses in vivo, the drug of this invention did not cause non-specific DNA damage, demonstrating good safety and targeting.

[0014] 5. Providing a basis for clinical translation: The invention has shown significant efficacy in both in vivo and in vitro experiments, providing direct experimental evidence for the clinical application of this small molecule in the treatment of oxidative stress-related liver diseases. Attached Figure Description

[0015] Figure 1 Small molecule TH10785 alleviates liver fibrosis in BDL mouse model; (A) BDL experimental design: Bile duct ligation was used to induce cholestasis in wild-type and OGG1 knockout mice. TH10785 and control corn oil were then administered intraperitoneally every other day. Liver and serum were collected 20 days later. (B) Survival status of BDL mice. (C) Liver damage levels were assessed using serum ALT and AST in the BDL mouse model. (DE) Immunohistochemistry / HE staining (D) and statistical analysis (E) reflected liver damage, cirrhosis (Sirius red, α-SMA staining), OGG1 levels, and DNA damage (gH2AX) in mice.

[0016] Figure 2 Results of small molecule TH10785 reducing liver inflammation in BDL mouse model; (AB) BDL models were established in wild-type and OGG1 knockout mice. HE and F4 / 80 staining were used to reflect inflammatory cell infiltration, macrophage infiltration (A), and statistical results (B). (CD) In ​​the BDL mouse model, M1 macrophage aggregation in the portal area (C) and statistical analysis (D). (E) BDL models were established in wild-type and OGG1 knockout mice, and the protein levels of various inflammatory cytokines were detected in mouse serum. (F) BDL models were established in wild-type and OGG1 knockout mice, and the mRNA expression levels of various inflammatory cytokines were detected using qPCR. Figure 3 Figure: Experimental results of small molecules promoting oxidative DNA repair in hepatocytes; (AB) Primary hepatocytes were isolated from wild-type and OGG1 knockout mice after intraperitoneal injection of TH10785. Intracellular oxidative damage was then induced using H2O2, and the content of oxidative bases in the cells was compared using a comet assay. The content of remaining intracellular oxidative bases was compared after 30 and 60 minutes of repair in different treatments. Characteristic results (A) and statistical results (B) are shown. (CD) In ​​primary hepatocytes, DNA oxidative damage was induced using cholic acid (simulating cholestasis). Hepatocytes were then subjected to DMSO, TH10785, APE1 inhibitor, and TH10785 + APE1 inhibitor for 30, 60, and 90 minutes of repair, respectively. Immunofluorescence was used to compare OGG1 aggregation (reflecting DNA repair) and ARP probe response at the AP site (an intermediate step in DNA oxidative damage repair). (E) Primary hepatocytes were isolated from wild-type and OGG1 knockout mice after intraperitoneal injection of TH10785. DNA oxidative damage was induced using bile acid (simulating cholestasis). Hepatocytes were then subjected to treatments with DMSO, TH10785, an APE1 inhibitor, and TH10785 + an APE1 inhibitor for 30, 60, and 90 minutes, respectively. Overall DNA damage and APE1 levels were assessed using gH2AX. The results showed that TH10785 rapidly cleared oxidized bases from hepatocytes.

[0017] Figure 4 Figure: Results of small molecule TH10785 inhibiting inflammatory response in MASH mouse model; (A) Schematic diagram of experimental design: MASH model was established in mice by administering a CDAA-HFD diet. Mice were intraperitoneally injected with TH10785 or control corn oil every other day. After 8 weeks, mice were sacrificed and serum was collected. (BC) Schematic diagram of the structures of TH10785 (B) and TH5487 (C). (D) In ​​wild-type and OGG1 knockout mice, gH2AX, F4 / 80, and HE staining were used to detect the level of DNA damage, macrophage infiltration, and immune cell infiltration in the liver. (EF) Analysis of the above staining results, including fatty liver level, DNA damage level (E), macrophage infiltration, and immune cell infiltration (F). (G) ELISA method was used to detect the protein expression of various inflammatory cytokines in the serum of mice in the MASH model.

[0018] Figure 5 Results of small molecule TH10785 inhibiting M1 polarization; (A) mRNA expression levels of various inflammatory cytokines in the liver of mice in the MASH model. (BC) Immunofluorescence detection of the content of M1 and M2 macrophages in the liver tissue of MASH model mice (B) and quantitative results of M1 macrophages (C). (D) TH10785 and TH5487 can inhibit the activation of RAW246.7 macrophage cell line and primary mouse macrophages, and the required concentration of TH10785 is significantly lower than that of TH5487. However, TH10785 has no inhibitory effect on macrophages isolated from OGG1 knockout mice. (E) LPS can induce macrophage M1 activation, while TH10785, TH10785+PNKP inhibitor and TH5487 can effectively inhibit the expression of 78 important pro-inflammatory genes.

[0019] Figure 6 : Results of small molecule TH10785 inhibiting B cell activation; (AB) CD95 (Fas) labels live cells, CD69 labels activated B cells; (CD) CD38 labels activated B cells, CD27 labels mature B cells, double positive indicates plasma cells; (EF) GL-7 labels germinal center B cells (one type in the B cell activation process), Fas labels live cells. Detailed Implementation

[0020] This invention provides a novel use of a small molecule OGG1 activator in the preparation of drugs for treating inflammatory liver diseases. This small molecule (TH10785) can activate the DNA repair enzyme OGG1 and induce its β- and δ-cleavage activities, thereby endowing OGG1 with new catalytic functions. By enhancing the rate of oxidative DNA repair and promoting PNKP1-mediated DNA break repair, the drug of this invention can effectively reduce the level of oxidative damage in hepatocytes, inhibit inflammatory responses, and ultimately achieve therapeutic effects on metabolic-associated steatohepatitis (MASH), cholestatic liver disease, and autoimmune hepatitis.

[0021] The main technical features of this invention include, but are not limited to, the following aspects: 1. Signal regulation characteristics: By enhancing DNA repair capabilities, the drug of this invention can significantly inhibit the sustained activation of NF-κB and MAPK signaling pathways, reduce the production of pro-inflammatory factors such as TNF-α, IL-1β, and CCL2, and inhibit M1 macrophage-mediated inflammatory responses.

[0022] 2. Immune regulation characteristics: The drug of the present invention can inhibit the excessive activation of B cells in an autoimmune hepatitis model, reduce the proportion of activated B cells (CD19⁺) and plasma cells in liver tissue, thereby alleviating immune-mediated liver damage.

[0023] 3. Indications: The drugs of this invention are applicable to a variety of liver diseases with oxidative stress and inflammatory response as the core pathological mechanisms, including but not limited to: metabolic-associated steatohepatitis (MASH / NASH); cholestatic liver diseases (mainly including biliary atresia, primary sclerosing cholangitis, and primary biliary cholangitis); autoimmune hepatitis; and other chronic liver fibrosis diseases accompanied by DNA oxidative damage (such as hepatitis B).

[0024] 4. Pharmacological characteristics: In animal models, the drug of this invention can significantly reduce serum ALT and AST levels and alleviate the degree of inflammatory infiltration and fibrosis in liver tissue; at the same time, immunohistochemical and transcriptomic analyses have verified its inhibitory effects on inflammatory pathways and B cell activation pathways.

[0025] 5. Safety and specificity characteristics: The drug of this invention does not affect the basal recognition site of OGG1, nor does it induce non-specific DNA breaks, and has good tissue tolerance and metabolic stability at effective doses.

[0026] The technical solutions and effects of this application will be further described in detail below with reference to the embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are merely for explaining the invention and are not intended to limit the invention.

[0027] In this application, all experimental methods, reagents, antibodies, and instruments used were performed according to standard laboratory operating procedures; statistical analysis was performed using mean ± SEM, and inter-group comparisons were performed using Student's t-test or ANOVA (n-value and p-value are indicated in the figures). The following "Detection Results" are shown in the provided figures (…). Figures 1-6 The statement is based on the information provided.

[0028] Example 1: TH10785 reduces liver fibrosis and is OGG1 dependent. Experimental Construction and Grouping Animal materials: C57BL / 6 wild-type mice and OGG1 knockout (OGG1- / -) mice were purchased from Cyagen Biosciences (https: / / www.cyagen.cn / ), aged 6–8 weeks, and randomly assigned to groups.

[0029] Grouping example (n≥5 per group): Sham + corn oil; BDL + Corn Oil (Model Control); BDL + TH10785 (1 mg / kg, intraperitoneal injection, once every other day); BDL + TH10785 (5 mg / kg, intraperitoneal injection, every other day).

[0030] The same grouping was repeated for OGG1- / - mice to detect OGG1 dependence.

[0031] Bile duct ligation surgery: Mice were anesthetized (anesthesia protocol was selected according to the animal ethics requirements of the laboratory), the common bile duct was exposed by laparotomy, and the proximal end was ligated and cut (BDL); in the Sham group, only the duct was exposed but not ligated. Postoperatively, mice were kept warm, and necessary analgesia and nursing care were provided.

[0032] Dosing regimen and endpoint TH10785 was dissolved in corn oil to prepare an injection solution; the drug was started after surgery and administered intraperitoneally every other day for 20 days (some were extended to 30 days for survival observation).

[0033] Endpoint assessment: Animals were euthanized on postoperative day 20 (or 30) and serum and liver tissue were collected.

[0034] Detection methods Survival record: Intraoperative to endpoint survival assessment and Kaplan–Meier curve plotting ( Figure 1 B).

[0035] Serology: Blood collection and centrifugation to determine ALT and AST ( Figure 1 C).

[0036] Histology: Hematoxylin and eosin (HE), Sirius Red, and α-SMA immunohistochemistry were performed on paraffin sections of liver tissue. Figure 1 DE is used to assess markers of tissue necrosis, collagen deposition, and stellate cells / fibrosis.

[0037] DNA damage and repair markers: Immunohistochemical detection of overall DNA damage levels in hepatocytes using γH2AX. Figure 1 DE).

[0038] Test results TH10785 (1 mg / kg and 5 mg / kg) significantly improved the survival rate of BDL mice. Figure 1 B); The serum ALT / AST ratio in the TH10785 treatment group was significantly lower than that in the BDL + corn oil group. Figure 1 C); HE, Sirius Red, and α-SMA staining showed that TH10785 significantly reduced liver tissue necrosis and fibrosis. Figure 1 DE); The number of γH2AX positive cells decreased significantly in the TH10785 group. Figure 1 D); In OGG1- / - mice, TH10785 failed to significantly improve the above indicators, suggesting that the therapeutic effect is dependent on OGG1.

[0039] in conclusion In a BDL model, TH10785 administration at 1–5 mg / kg (intraperitoneal injection, every other day) reduced cholestasis-induced liver injury and fibrosis, and decreased oxidative DNA damage; the therapeutic effect was absent or attenuated in OGG1-deficient animals, indicating that the mechanism depends on the OGG1-related pathway (see [link to relevant documentation]). Figure 1 , Figure 2 ).

[0040] Example 2: TH10785 reduces liver inflammation and is OGG1 dependent. Experimental setup and grouping: Same as in Example 1.

[0041] Detection methods Histology: HE staining was used to observe inflammatory cell infiltration, and F4 / 80 immunohistochemistry was used to detect macrophage infiltration. Figure 2 AB).

[0042] M1 macrophage localization and quantification: M1 markers (e.g., co-expression of CD86 and F4 / 80) in the portal venous area (portal area) were analyzed by immunofluorescence or IHC, and the number and proportion of M1 aggregation foci were counted. Figure 2 CD).

[0043] Inflammatory factor detection: Multiple pro-inflammatory cytokines in serum were detected using protein immunoassay (ELISA / Luminex). Figure 2 E); The expression of multiple inflammatory cytokines in liver tissue was detected by qPCR using mRNA levels. Figure 2 F).

[0044] Test results HE and F4 / 80 staining in the TH10785 treatment group showed a significant reduction in inflammatory cell and macrophage infiltration. Figure 2 AB); The number of M1 macrophages focusing in the portal vein area was significantly decreased in the TH10785 group. Figure 2 CD); The protein and mRNA levels of various pro-inflammatory cytokines in serum and liver tissue were significantly decreased in the TH10785 group. Figure 2 EF); The above-mentioned inhibitory effects were significantly weakened or disappeared in OGG1- / - mice, further supporting the OGG1-dependent mechanism.

[0045] in conclusion TH10785 exerted an anti-inflammatory effect in the BDL model by inhibiting the infiltration of inflammatory cells in the liver, reducing M1 macrophage aggregation, and downregulating the expression of pro-inflammatory factors (see [link to article]). Figure 2 ).

[0046] Example 3: TH10785 promotes oxidative DNA repair in hepatocytes and is OGG1 dependent. Experimental Construction In wild-type and OGG1- / - mice, TH10785 was administered (in vivo, 1 mg / kg or 5 mg / kg, intraperitoneal injection, every other day), and the mice were sacrificed 8-12 hours after administration and primary hepatocytes were isolated; or the cells were directly pretreated in vitro in the cell line (HEP3B).

[0047] Oxidative damage induction and repair detection Induction: Oxidative DNA damage was induced by H2O2 (200 μM, 30 min) or bile acid (CA, 1 mM, 30 min).

[0048] Repair: Replace with a complete culture medium and take samples at 0, 30, 60, and 90 minutes.

[0049] Detection methods Comet experiment (including Fpg / FpG recognition of oxidized bases) to quantify tail moments to assess oxidized base residues ( Figure 3 AB).

[0050] Immunofluorescence assay of OGG1 foci (reflecting OGG1 recruitment / repair dynamics) and ARP-Streptavidin-FITC probe detection of AP sites (repair intermediates) over time. Figure 3 CD).

[0051] γH2AX immunofluorescence was used to assess the decrease in overall DNA damage over time. Figure 3 E).

[0052] Test results Comet assays showed that primary hepatocytes treated with TH10785 exhibited significantly lower tail moments than the control group during the 30 and 60-minute repair phases, indicating that oxidized bases were cleared more rapidly. Figure 3 (AB); This effect disappears or is significantly weakened in OGG1- / - cells.

[0053] ARP probe and OGG1 foci detection: In the TH10785 treatment group, changes in OGG1 foci and dynamics of AP sites were observed after short-term induction (30 min) (AP initially increased and then rapidly decreased over time), suggesting an acceleration of the intermediate repair step. Figure 3 CD).

[0054] γH2AX: Overall DNA damage significantly decreased with repair time in the TH10785 group, indicating that TH10785 can rapidly clear oxidized bases in hepatocytes. Figure 3 E).

[0055] in conclusion TH10785 can accelerate the clearance of H2O2 or bile acid-induced oxidative DNA damage by hepatocytes, manifested by a rapid decrease in comet tail moment, ARP signaling, and γH2AX; OGG1- / - cells lack this effect, supporting an OGG1-dependent enhancement mechanism of repair (see...). Figure 3 ).

[0056] Example 4: TH10785 inhibits inflammatory response and fibrosis, and is OGG1 dependent. Model establishment, drug administration and detection Model: MASH was established using a CDAA-HFD diet, and mice were fed continuously for 8 weeks.

[0057] Administration: TH10785 or corn oil was administered intraperitoneally as a control, every other day for 8 weeks (administration was started at the beginning of modeling or after the model stabilized to examine the preventive / therapeutic effects).

[0058] Detection: Endpoints included serum (ELISA) and liver tissue (HE, F4 / 80, γH2AX). Analysis included the degree of fatty liver, DNA damage level, and macrophage and immune cell infiltration. Figure 4 DF, G).

[0059] Test results The TH10785 treatment group showed a significant decrease in liver γH2AX signal, F4 / 80 infiltration, and HE-based fat / inflammation score. Figure 4 DF); Serum ELISA showed decreased levels of multiple pro-inflammatory cytokines (DF); Figure 4 G).

[0060] In OGG1- / - mice, the anti-inflammatory and repair effects of TH10785 were significantly weakened or disappeared.

[0061] in conclusion In the CDAA-HFD-induced MASH model, TH10785 inhibited liver inflammation and DNA damage and reduced the expression of pro-inflammatory cytokines, supporting its therapeutic potential for MASH (see [link to relevant documentation]). Figure 4 ).

[0062] Example 5: TH10785 inhibits M1 polarization and pro-inflammatory gene expression in an OGG1-dependent manner. Experimental Construction Cells: RAW246.7 macrophage cell line and primary mouse bone marrow-derived macrophages (BMDM).

[0063] Stimulation: LPS (500 ng / mL) induces M1 polarization, and treatment lasts for 16-24 hours.

[0064] Treatments: TH10785 cells (low nM to several concentration gradients), reference compound TH5487 cells (μM gradients), and PNKP inhibitor / OGG1- / - cells as controls.

[0065] Detection methods Flow cytometry: Detection of M1 phenotype (CD86) + F4 / 80 + ) and M2 (CD206) + F4 / 80 + )Proportion( Figure 5 BC).

[0066] Gene expression: qPCR or array detection of changes in the expression of 78 pro-inflammatory genes ( Figure 5 E).

[0067] Test results Both TH10785 and TH5487 can inhibit LPS-induced M1 polarization; however, the effective concentration of TH10785 is significantly lower than that of TH5487 (cell experiments show that TH10785 is effective at low nM levels, while TH5487 is effective at μM levels), and TH10785 is ineffective in OGG1- / - macrophages. Figure 5 D).

[0068] Multiple pro-inflammatory genes induced by LPS were inhibited by treatment with TH10785, TH10785+PNKP inhibitors, and TH5487, indicating that the inhibitory effect of TH10785 on pro-inflammatory gene expression is related to the aforementioned repair / pathway. Figure 5 E).

[0069] in conclusion TH10785 can inhibit macrophage M1 polarization and pro-inflammatory gene expression at low concentrations, and its effect is dependent on OGG1 (see [link to article]). Figure 5 ).

[0070] Example 6: Validation of an Inhibition of B Cell Activation and an Autoimmune Hepatitis Model In vitro B cell activation experiment Materials: Human peripheral blood PBMCs, CD19 was obtained by magnetic bead sorting. + B cells.

[0071] Activation: Stimulation with activating conditions (such as anti-IgM / IgG, CD40L, IL-4 / IL-21, etc.) to induce B cell activation and plasma cell differentiation.

[0072] Treatment: Add TH10785 (several gradients) to the activation system and incubate for 3-5 days.

[0073] Detection: Flow cytometry was used to detect Fas (CD95) (used to distinguish between live cells and activated cells), CD69 (an early activation marker), and CD38 and CD27 (used to identify CD38⁺CD27⁺ plasmablasts / plasma cells). B cell activation rate and plasma cell formation rate were calculated based on the expression levels of each marker. Figure 6 AD).

[0074] A mouse model of autoimmune hepatitis (AAV-IL-12) Modeling: Autoimmune hepatitis-like pathology was established by intraperitoneal injection of AAV-IL-12; TH10785 or control was administered (intraperitoneal injection, once every other day).

[0075] Endpoint assessment: Spleen / peripheral blood was collected, and the proportion of activated plasma cells was determined by flow cytometry. Figure 6 EF), and detect liver pathological indicators.

[0076] Test results In vitro: TH10785 can inhibit the activation of human PBMC-derived B cells and plasma cell formation (flow cytometry results and statistical illustrations). Figure 6 AD); In vivo: In the AAV-IL-12 mouse model, the proportion of activated plasma cells (GL-7⁺ and Fas⁺ labeled activated / germinal center B cells) in the spleen of the TH10785 treatment group was significantly decreased. Figure 6 EF) suggests that it has an inhibitory effect on B cell-mediated damage associated with autoimmune hepatitis.

[0077] in conclusion TH10785 inhibits B cell activation and plasma cell differentiation in vitro and reduces activated plasma cells in an AAV-IL-12 autoimmune hepatitis model, supporting its therapeutic use in the treatment of autoimmune hepatitis (see [link to relevant documentation]). Figure 6 ).

[0078] The small molecule of this invention enhances the β,δ-cleavage activity of OGG1, thereby achieving efficient repair of oxidative DNA damage, thus reducing ROS accumulation and hepatocyte damage; it inhibits OGG1-mediated transcription of pro-inflammatory genes and regulates M1 / M2 macrophage polarization; and it inhibits B cell activation, thereby reducing the inflammatory response of autoimmune hepatitis.

[0079] The small molecules of this invention can be prepared into various drug dosage forms, including but not limited to solutions, injections, oral solid dosage forms, or sustained-release formulations, to meet different clinical needs.

[0080] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. Application of OGG1 small molecule agonists in the preparation of drugs for the treatment of inflammatory liver diseases; The OGG1 small molecule agonist is TH10785.

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