Use of slc13a2 inhibitors in the preparation of drugs for preventing and treating acute liver injury and liver failure

Abstract

The application discloses application of an SLC13A2 inhibitor in preparation of a medicine for preventing and treating acute liver injury and liver failure. The application firstly finds that SLC13A2 is a key transport protein that is specifically down-regulated in the early stage of acute liver injury, and can be used as a specific metabolic target for preventing and treating acute liver injury and liver failure. Meanwhile, the application firstly clarifies a core pathogenic pathway of SLC13A2-succinic acid-FASN succinoylation-lipid abnormal synthesis, and clearly defines the key role of the core pathogenic pathway in driving liver injury progression and promoting liver failure occurrence, thereby providing theoretical support for metabolic targeted treatment. On this basis, the application proposes that a compound with SLC13A2 inhibitory activity is used for preparing a medicine for preventing and treating acute liver injury and liver failure, so that the liver injury process can be blocked from the metabolic source, and the risk of liver failure occurrence can be reduced, and the application has target precision, a wide application range and outstanding clinical conversion value.

Description

Technical Field

[0001] This invention relates to the application of SLC13A2 inhibitors, and more particularly to the application of SLC13A2 inhibitors in the preparation of drugs for the prevention and treatment of acute liver injury and liver failure. Background Technology

[0002] Acute liver injury (ALI) is a serious liver disease induced by multiple factors, characterized by rapid onset, rapid progression, and high mortality, and has become a significant global public health burden. Currently, the clinical incidence of ALI is large, with drug abuse, exposure to chemical toxins, and excessive use of chemotherapy drugs being major contributing factors. Among these, acetaminophen (APAP) overdose is currently the most prevalent cause. Excessive APAP intake is metabolized in the liver to produce the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which significantly depletes the glutathione reserves in hepatocytes, inducing mitochondrial dysfunction, oxidative stress, and cell necrosis. In severe cases, it can rapidly progress to acute liver failure, endangering life.

[0003] Currently, clinical treatment options for acute liver injury are very limited. There are no specific drugs targeting the pathogenesis, and treatments often rely on anti-inflammatory and conventional hepatoprotective drugs for symptomatic relief. These only alleviate surface symptoms and cannot block the damage process at the metabolic level, resulting in limited overall therapeutic efficacy and a significant unmet clinical need. The existing standard treatment, N-acetylcysteine ​​(NAC), is only effective within a very short time window after APAP overdose; its efficacy significantly decreases after 10 hours, narrowing its clinical applicability. Furthermore, NAC is only effective against APAP-induced liver injury and is almost ineffective against acute liver injury caused by various factors such as carbon tetrachloride (CCl4), heavy metals, and other drugs. Current clinical treatments fail to fundamentally block hepatocyte death and liver damage progression, lacking etiological treatment strategies targeting the common pathological mechanisms of acute liver injury. Therefore, it is urgent to clarify the core pathogenesis of acute liver injury and identify common therapeutic targets applicable to multi-etiological acute liver injury, providing a theoretical basis for developing novel, safe, and effective therapeutic drugs.

[0004] Metabolic reprogramming is a key biological process regulating the progression of acute liver injury and determining the survival or death of hepatocytes. Lipid metabolism disorder is considered one of the core pathological features of acute liver injury. Under normal physiological conditions, hepatocyte lipid synthesis, fatty acid oxidation, and lipid transport maintain a dynamic balance. However, under acute liver injury conditions, mitochondrial function is impaired, fatty acid β-oxidation is significantly inhibited, and lipid synthesis is abnormally enhanced, leading to a large accumulation of lipid droplets in hepatocytes. This induces lipotoxicity, endoplasmic reticulum stress, and inflammatory responses, further amplifying liver damage. Numerous studies have confirmed a significant positive correlation between the degree of lipid accumulation and the severity of liver injury, and restoring lipid metabolic homeostasis can significantly reduce hepatocyte damage. However, there are currently no specific therapeutic targets available for clinical use that can effectively restore lipid metabolic homeostasis and inhibit lipotoxic damage, hindering the development of targeted drugs for acute liver injury.

[0005] The tricarboxylic acid (TCA) cycle is a core hub of cellular energy metabolism, providing crucial precursors for the biosynthetic pathways of fatty acids, cholesterol, and amino acids. It is a critical node connecting mitochondrial function, oxidative stress, lipid metabolism, and cell death. In acute liver injury, mitochondrial damage leads to TCA cycle dysfunction, resulting in imbalances in the homeostasis of key metabolic intermediates such as succinate, citrate, and α-ketoglutarate, further exacerbating oxidative stress and lipid metabolism abnormalities. Studies have shown that TCA cycle-related metabolic flux disturbances are key predictors of liver injury and elevated transaminase levels, and maintaining TCA cycle metabolite balance is crucial for mitigating drug- or toxin-induced liver injury. However, current research largely focuses on overall TCA cycle functional alterations, with limited understanding of the molecular mechanisms underlying TCA cycle metabolic intermediate transport, homeostasis regulation, and their impact on lipid synthesis and liver injury. Particularly, there is a lack of research on key transporter protein targets mediating transmembrane transport of TCA cycle metabolites and regulating lipid metabolism.

[0006] In summary, existing drugs for acute liver injury have a narrow applicability and cannot block the progression of the injury; there is a lack of targeted drugs applicable to multiple etiologies with clear mechanisms; there are no effective targets to regulate the core pathological feature of acute liver injury—lipid metabolism disorder; and existing FASN inhibitors have off-target risks and safety concerns; the transport regulation mechanism and key targets of the abnormal tricarboxylic acid cycle that connects mitochondrial damage and lipid disorder are still unclear. Summary of the Invention

[0007] Purpose of the invention: The purpose of this invention is to provide the application of SLC13A2 inhibitors in the preparation of drugs for the prevention and treatment of acute liver injury and liver failure.

[0008] Technical solution: This invention provides the application of SLC13A2 inhibitors in the preparation of drugs for the prevention and treatment of acute liver injury and liver failure.

[0009] Solute carriers (SLCs) are one of the largest families of membrane transport proteins in the human body. Among them, SLC13A2 is a novel therapeutic target for acute liver injury. It is specifically downregulated in the early stages of liver injury and is a key transport protein regulating hepatic metabolic disorders. It primarily mediates the uptake of succinate and other tricarboxylic acid cycle intermediates by hepatocytes, thereby exacerbating hepatocyte damage through succinate transport and aggravating the pathological process of acute liver injury induced by various factors. This invention reveals for the first time the core role of SLC13A2 in acute liver injury and its complete regulatory mechanism, establishing a direct link between SLC13A2-succinate-lipid metabolism disorders and acute liver injury. Based on this, this invention expands the application of SLC13A2 inhibitors to the treatment of drug- and toxin-induced acute liver injury for the first time, clarifying its therapeutic effect on hepatocyte damage induced by toxins such as carbon tetrachloride and acetaminophen, thus broadening its application scope.

[0010] Furthermore, the acute liver injury and liver failure may be caused by drugs or toxins.

[0011] Furthermore, the drug or poison is carbon tetrachloride or acetaminophen.

[0012] Furthermore, the SLC13A2 inhibitor reduces the degree of liver necrosis and inhibits transaminase levels and liver tissue TG levels.

[0013] Furthermore, the active ingredient of the drug is an SLC13A2 inhibitor or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof.

[0014] Furthermore, the drug is a metabolic-targeting drug.

[0015] Furthermore, the metabolism in question is lipid metabolism.

[0016] Furthermore, the drug also includes a pharmaceutically acceptable carrier or excipient, and is formulated into a pharmaceutically acceptable dosage form.

[0017] Furthermore, the dosage form is an injection, lyophilized powder, injection, tablet, or capsule.

[0018] Furthermore, the SLC13A2 inhibitor is preferably N-(4-pentylcinnamoyl)anthranilic acid (ACA) or its structural analogues.

[0019] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0020] This invention is the first to discover that SLC13A2 is a key transporter protein specifically downregulated in the early stages of acute liver injury, and can serve as a specific metabolic target for the prevention and treatment of acute liver injury and liver failure. Simultaneously, it elucidates for the first time the core pathogenic pathway of SLC13A2-succinate-FASN succinylation-abnormal lipid synthesis, clarifying its crucial role in driving liver injury progression and promoting liver failure, providing theoretical support for metabolic targeted therapy. Based on this, this invention proposes using compounds with SLC13A2 inhibitory activity to prepare drugs for the prevention and treatment of acute liver injury and liver failure. This can block the progression of liver injury at its metabolic source and reduce the risk of liver failure, solving the technical problems of the lack of specific drugs targeting lipid metabolism disorders in the treatment of acute liver injury and the limited efficacy of traditional hepatoprotective methods, while avoiding the off-target effects and safety risks of directly inhibiting FASN. This invention has precise targeting, broad applicability, and outstanding clinical translational value. Attached Figure Description

[0021] Figure 1 A schematic diagram illustrating the administration of the SLC13A2 inhibitor ACA to mitigate the effects of carbon tetrachloride-induced acute liver injury;

[0022] Figure 2 A schematic diagram illustrating the effect of the SLC13A2 inhibitor ACA on the degree of liver necrosis (A: HE staining of liver tissue; B: statistical results of necrosis area; data are expressed as mean ± standard error (mean ± SEM), and one-way ANOVA and Tukey post-hoc test were used for comparisons between groups; compared with the carbon tetrachloride model control group, p>0.05 was considered no statistical difference (ns), p<0.05 was considered significant (*), and p<0.01 was considered extremely significant (**)).

[0023] Figure 3 A schematic diagram illustrating the effect of the SLC13A2 inhibitor ACA on transaminase levels (A represents serum ALT level; B represents serum AST level; data are expressed as mean ± standard error (mean ± SEM), and one-way ANOVA and Tukey post-hoc test were used for comparisons between groups; compared with the carbon tetrachloride model control group, p>0.05 was considered not statistically significant (ns), p<0.05 was considered significantly significant (*), and p<0.01 was considered extremely significant (**)).

[0024] Figure 4 A schematic diagram illustrating the effect of the SLC13A2 inhibitor ACA on lipid levels (A represents serum TG level; B represents liver TG level; C represents serum TC level; D represents liver TC level; data are expressed as mean ± standard error (mean ± SEM), and one-way ANOVA and Tukey post-hoc test were used for comparisons between groups; compared with the carbon tetrachloride model control group, p>0.05 was considered no statistical difference (ns), p<0.05 was considered significant (*), and p<0.01 was considered highly significant (**)). Detailed Implementation

[0025] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0026] Example 1

[0027] This embodiment uses a mouse model to verify the therapeutic effect of the SLC13A2 inhibitor on acute liver injury. The mouse acute liver injury model was induced by carbon tetrachloride. The SLC13A2 inhibitor used was N-(4-pentylcinnamamide)-o-aminobenzoic acid (ACA).

[0028] Experimental animals: Male C57BL / 6J mice, 6-8 weeks old, weighing 18-22g, provided by the Institute of Model Animals, Nanjing University. Laboratory temperature: 20-22℃, relative humidity: 40%-60%, ventilation fan provided, natural light: 12h / day. Mice were housed in cages of 6, with cages cleaned every three days. Mice were randomly divided into 3 groups of 6 each.

[0029] Main reagents and usage: 1. Carbon tetrachloride (Catalog No.: C805327, Manufacturer: Macklin): Prepared fresh at 0.75 mL / kg with olive oil before use, and administered intraperitoneally to establish an acute liver injury model in mice. 2. ACA (Catalog No.: A275778, Manufacturer: Aladdin): Prepared at 15 mg / kg and 30 mg / kg; administered via intraperitoneal injection; dosage: 0.05 ml / 10 g mouse. See the experimental diagram below. Figure 1 .

[0030] Sampling and testing: Forty-eight hours after carbon tetrachloride modeling, blood was collected from the retro-orbital venous plexus. Serum was collected by centrifugation at 5000g for 10 minutes at 4 degrees Celsius, and ALT, AST, TG, and TC were measured. Mice were euthanized by cervical dislocation, and the liver was quickly removed. Half of the liver was fixed in formalin and stained with hematoxylin and eosin (HE), while the other half was quickly fixed in liquid nitrogen. The liver tissue was then stored at -80°C for the detection of TG and TC.

[0031] The results showed that ACA significantly inhibited carbon tetrachloride-induced acute liver injury. This was demonstrated by ACA significantly reducing the area of ​​liver necrosis in mice with acute liver injury. Figure 2 High-dose ACA significantly inhibited serum ALT and AST levels in mice with acute liver injury. Figure 3 ) and TG levels in liver tissue ( Figure 4 ).

Claims

1. Application of SLC13A2 inhibitors in the preparation of drugs for the prevention and treatment of acute liver injury and liver failure.

2. The application according to claim 1, characterized in that, The causes of acute liver injury and liver failure are drugs or toxins.

3. The application according to claim 2, characterized in that, The drug or poison is carbon tetrachloride or acetaminophen.

4. The application according to claim 1, characterized in that, The SLC13A2 inhibitor reduces the degree of liver necrosis and inhibits transaminase levels and liver tissue TG levels.

5. The application according to claim 1, characterized in that, The active ingredient of the drug is an SLC13A2 inhibitor or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof.

6. The application according to claim 1, characterized in that, The drug is a metabolic-targeting drug.

7. The application according to claim 6, characterized in that, The metabolism in question is lipid metabolism.

8. The application according to claim 1, characterized in that, The drug also includes a pharmaceutically acceptable carrier or excipient and is formulated into a pharmaceutically acceptable dosage form.

9. The application according to claim 8, characterized in that, The dosage form is an injection, lyophilized powder, injection, tablet, or capsule.

10. The application according to any one of claims 1-9, characterized in that, The SLC13A2 inhibitor is N-(4-pentylcinnamamide)o-aminobenzoic acid or its structural analogue.

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