Application of ursodesoxychoberberine in preparation of anti-lung cancer drugs

Abstract

The invention discloses application of ursodesoxychoberberine in preparation of anti-lung cancer drugs, and relates to the technical field of cancer treatment, ursodesoxychoberberine (BU) shows significant activity in anti-inflammatory and comprehensive metabolic regulation aspects, the progress of ursodesoxychoberberine (BU) mainly focuses on adaptation diseases such as type 2 diabetes mellitus (T2DM), metabolism-related steatohepatitis (MASH) and the like, and the ursodesoxychoberberine (BU) shows significant activity in anti-inflammatory and comprehensive metabolic regulation aspects. However, it is still blank in the lung cancer treatment research field, and the effect and application of the compound in the lung cancer field need to be expanded urgently. The invention provides an application of ursodesoxychoberberine in preparation of an anti-lung cancer drug. The ursodesoxychoberberine can inhibit lung cancer cell proliferation.

Description

Technical Field

[0001] This invention relates to the field of lung cancer technology, specifically to the application of ursodeoxycholic acid in the preparation of anti-lung cancer drugs. Background Technology

[0002] Ursodeoxycholic acid berberine (HTD1801, BU) is a globally innovative molecular entity formed by ursodeoxycholic acid and berberine through ionic bonds. It targets the gut-hepatic system through a dual mechanism of activating AMPK and inhibiting the NLRP3 inflammasome, exerting anti-inflammatory and comprehensive metabolic regulatory effects. Its research and development progress mainly focuses on indications such as type 2 diabetes mellitus (T2DM) and metabolic-associated steatohepatitis (MASH).

[0003] In the treatment of type 2 diabetes (TDM): Both Phase III clinical trials of HTD1801 in China (SYMPHONY 1 and SYMPHONY 2) met the primary efficacy endpoint and multiple secondary endpoints. Studies showed that after 24 weeks of treatment, HTD1801 significantly reduced glycated hemoglobin (HbA1c) by 1.2%-1.3%, and improved blood lipids (e.g., reducing LDL-C) and reduced inflammation (e.g., reducing hs-CRP), demonstrating its "multi-effect" properties.

[0004] (2) Regarding other metabolic diseases: HTD1801 has demonstrated efficacy in the MASH Phase IIa study, and its global multicenter Phase IIb clinical trial results are expected to be released in 2025. Simultaneously, studies also suggest its therapeutic potential in weight loss, severe hypertriglyceridemia (SHTG), and primary sclerosing cholangitis (PSC). In terms of safety, HTD1801 is well-tolerated, with the most common adverse reactions being gastrointestinal reactions, and a low risk of hypoglycemia. Overall, HTD1801, as a multi-target drug with a novel mechanism of action, shows the potential to provide comprehensive benefits in the treatment of metabolic diseases. Its development is progressing smoothly, and its application for marketing authorization in the T2DM indication is nearing completion.

[0005] Lung cancer is characterized by high mortality and morbidity rates, and its widespread global distribution, seriously impacting human health. Research on lung cancer has always been a key focus and challenge in cancer research. The occurrence and development of lung cancer are closely related to inflammation and tumor metabolism. Chronic inflammation and abnormal tumor metabolism not only participate in the initiation of lung cancer but also drive its progression and metastasis.

[0006] On the one hand, chronic inflammation is a significant contributing factor and driving force of lung cancer. Persistent inflammation in the lungs (such as that caused by chronic obstructive pulmonary disease or tuberculosis) damages lung tissue. Reactive oxygen species and cytokines (such as interleukins) released by inflammatory cells can lead to DNA damage and gene mutations, thereby promoting tumorigenesis. Furthermore, the tumor inflammatory microenvironment (composed of tumor cells, immune cells, and cytokines) plays a crucial role in lung cancer development. It supports tumor growth and metastasis by promoting angiogenesis, inhibiting apoptosis, inducing epithelial-mesenchymal transition (EMT), and helping tumor cells achieve immune escape. Notably, pulmonary dysbiosis may also further exacerbate inflammation and promote tumor development by activating immune cells such as γδT cells to secrete pro-inflammatory factors such as IL-17.

[0007] On the other hand, tumor metabolic reprogramming is a prominent feature of lung cancer. Lung cancer cells exhibit a unique metabolic pattern, preferentially obtaining energy through glycolysis even under oxygen-rich conditions. This metabolic shift not only provides a large amount of biosynthetic raw materials for cancer cell proliferation, but the resulting metabolites (such as lactic acid) can further shape an immunosuppressive tumor microenvironment, contributing to tumor progression. There is a close interaction between metabolism and inflammation. Certain substances produced by tumor cell metabolism (such as lipopolysaccharides and free fatty acids) can induce or maintain a chronic inflammatory state in the tumor site; conversely, inflammatory signals can also reprogram tumor cell metabolism. Therefore, intervention strategies targeting inflammation and metabolism (such as the use of anti-inflammatory drugs, antibiotics, or modulation of specific metabolic pathways) have become a new research direction in lung cancer treatment.

[0008] Based on the significant anti-inflammatory and comprehensive metabolic regulation activities demonstrated by ursodeoxycholic acid (BU), and considering the current lack of research on its application in lung cancer treatment, expanding the application of BU in lung cancer treatment has significant scientific research and clinical translational value. This invention systematically evaluates the inhibitory effect of BU on lung cancer progression through in vivo and in vitro experiments, aiming to explore its anti-tumor mechanism and provide a theoretical basis and experimental evidence for developing new strategies for BU in lung cancer treatment. Summary of the Invention

[0009] To address the aforementioned problems, this invention systematically evaluates the inhibitory effect of BU on lung cancer progression through in vivo and in vitro experiments, aiming to explore its anti-tumor mechanism in depth and provide a theoretical basis and experimental evidence for developing new strategies for the treatment of lung cancer using BU.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows: Application of ursodeoxycholic acid in the preparation of anti-lung cancer drugs.

[0011] The lung cancer in question is specifically non-small cell lung cancer.

[0012] According to the applications described above, ursodeoxycholic acid can inhibit the proliferation of lung cancer cells.

[0013] An anti-lung cancer drug comprising ursodeoxycholic acid and a pharmaceutically acceptable carrier or excipient.

[0014] The beneficial effects of this invention are: Based on the significant anti-inflammatory and comprehensive metabolic regulation activities demonstrated by ursodeoxycholic acid (BU), and considering the current lack of research on its application in lung cancer treatment, expanding the application of BU in lung cancer treatment has significant scientific research and clinical translational value. This invention systematically evaluates the inhibitory effect of BU on lung cancer progression through in vivo and in vitro experiments, aiming to explore its anti-tumor mechanism and provide a theoretical basis and experimental evidence for developing new strategies for BU in lung cancer treatment. Ursodeoxycholic acid (BU) significantly inhibits the proliferation of various lung cancer cells and tumor growth in in vivo lung cancer models, providing a theoretical basis and experimental evidence for developing new strategies for BU in lung cancer treatment. Attached Figure Description

[0015] Figure 1 This is a schematic diagram illustrating the inhibitory effect of BU on the growth of murine lung cancer cells.

[0016] Figure 2 This is a schematic diagram illustrating the inhibitory effect of BU on the growth of human lung cancer cells.

[0017] Figure 3 This is a schematic diagram illustrating the dynamic inhibitory effect of BU on the volume of subcutaneous lung tumors.

[0018] Figure 4 This is a schematic diagram illustrating the inhibitory effect of BU on the weight of subcutaneous lung tumors.

[0019] Figure 5 This is a schematic diagram illustrating the tumor epigenetic results of BU's inhibitory effect on lung cancer progression in vivo.

[0020] Figure 6 This is a schematic diagram showing the changes in mouse body weight.

[0021] Figure 7 This is a schematic diagram of the organ coefficient results for mice.

[0022] Figure 8 This is a schematic diagram of the results of orthogonal partial least squares discriminant analysis (OPLS-DA).

[0023] Figure 9 This is a schematic diagram of the results of differential metabolite enrichment analysis (KEGG).

[0024] Figure 10 This is a schematic diagram of the results of differential metabolite analysis of lipid components.

[0025] Figure 11 This is a schematic diagram of the results of proteomics analysis.

[0026] Figure 12 This is a schematic diagram showing the expression level of the differentially expressed protein Grb2 in tumor tissue.

[0027] Figure 13 A schematic diagram illustrating the potential mechanism of action of BU in inhibiting lung cancer. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. The components of the embodiments of this application described and shown in the accompanying drawings can generally be arranged and designed in various different configurations.

[0029] The inventors have discovered that ursodeoxycholic acid (BU) has shown significant activity in anti-inflammatory and comprehensive metabolic regulation. Its progress has mainly focused on indications such as type 2 diabetes mellitus (T2DM) and metabolic-associated steatohepatitis (MASH), but its application in the treatment of lung cancer is still a blank, and there is an urgent need to expand its role and application in the field of lung cancer.

[0030] Based on the above findings, this application proposes the application of ursodeoxycholic acid (BU) in the preparation of anti-lung cancer drugs. Given the significant anti-inflammatory and comprehensive metabolic regulation activities of BU, and considering the current lack of research on its application in lung cancer treatment, expanding the application of BU in lung cancer treatment has significant scientific research and clinical translational value. This invention systematically evaluates the inhibitory effect of BU on lung cancer progression through in vivo and in vitro experiments, aiming to deeply explore its anti-tumor mechanism and provide a theoretical basis and experimental evidence for developing new strategies for BU in lung cancer treatment.

[0031] Example 1: In vitro experiment See Figure 1 - Figure 13 This application discloses the use of ursodeoxycholic acid in the preparation of an anti-lung cancer drug, which can inhibit the proliferation of lung cancer cells and the growth of tumors in an in vivo lung cancer model. Specifically, the lung cancer in question is non-small cell lung cancer.

[0032] An anti-lung cancer drug comprising ursodeoxycholic acid and a pharmaceutically acceptable carrier or excipient.

[0033] Carriers or excipients include, but are not limited to, the following types: Diluents: such as starch, pregelatinized starch, lactose, dextrin, sucrose, microcrystalline cellulose (MCC), mannitol, sorbitol, and inorganic calcium salts (such as calcium hydrogen phosphate, calcium carbonate, and calcium sulfate), are used to increase drug volume, improve formability, or improve taste. Adhesives: such as pure water, ethanol, starch paste, hydroxypropyl methylcellulose (HPMC) or hydroxymethylcellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), gelatin, etc., are used to improve the adhesion between powders and enhance the mechanical strength of the formulation. Lubricants, such as magnesium stearate (MS), micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol (PEG), sodium lauryl sulfate or magnesium salt, are used to improve the flowability and release properties of formulations during tableting, capsule filling and other processes.

[0034] The specific types and amounts of the excipients can be optimized and adjusted according to the target formulation (such as tablets, capsules, granules, pellets, solutions, etc.), administration route (oral, transdermal, topical, etc.), and the physicochemical properties of the BU, in order to achieve good pharmaceutical performance and biological stability.

[0035] In vitro experiments were conducted using the MTT assay to observe the application effects of the target drug BU on lung cancer cells. The specific experimental cells included: murine cells LLC (Cell Bank of the Chinese Academy of Sciences' Committee for Type Culture Collection; Catalog number: TCM 7) - and human lung cancer cells A549 (ATCC, Manassas, VA, USA; GF1009C), H23 (Cell Bank of the Chinese Academy of Sciences; SCSP-581), H1299 (ATCC, Manassas, VA, USA; GF1213C), H1975 (ATCC, Manassas, VA, USA; GF3167C). The reagents and consumables required for this experiment were as follows: high-glucose DMEM liquid medium (Thermo Fisher; Catalog number: C11995500BT), RPMI1640 medium (Thermo Fisher; Catalog number: C11875500BT), dimethyl sulfoxide (DMSO) (Macklin / Maclin; Catalog number: D915512-100ml), phosphate buffered saline (PBS) (Aladdin / Aladdin; Catalog number: P196987-500ml), premium fetal bovine serum Fetal Bovine Serum(Prime) (ExCell / Ekser; Catalog number: FSP500), double antibody (proteintech / Sanying Biology; Catalog number: 15613-1-AP), trypsin (Gibco; Catalog number: 25200-056), ursodeoxycholeberine (BU, HTD1801) (TargetMol / TaoShu; Catalog number: T67974), 96-well cell culture plates (not TC-treated) (Selected; Catalog number: 11520).

[0036] The experimental methods mainly included: The above-mentioned lung cancer cells in the logarithmic growth phase were inoculated into 96-well plates and cultured until they adhered, and then treated with different concentrations of BU for 72 h; Then, MTT solution was added to each well and incubated for another 4 h to allow live cells to fully form formazan crystals; Subsequently, the supernatant was discarded, and solvents such as dimethyl sulfoxide (DMSO) were added to dissolve these crystals; Finally, the absorbance values (OD values) of each well were measured using an enzyme-labeled instrument near the double wavelengths of 570 nm and 650 nm. This OD value is proportional to the number of live cells. By calculating the ratio of the experimental group to the blank control group, the inhibitory effect of BU on cell proliferation or activity can be quantitatively analyzed.

[0037] The results of in vitro experiments showed that, as Figure 1 、 Figure 2As shown, compound BU significantly inhibited lung cancer cell proliferation, with half-maximal inhibitory concentrations (IC50) below 20 μM for all tested cell lines. In particular, BU exhibited the most significant anti-proliferative activity against LLC, A549, and H23 cells, with IC50 values ​​of approximately 5 μM. These results suggest that BU has good development potential in inhibiting lung cancer cell proliferation.

[0038] Example 2: In vivo experiment In vivo experiments were conducted to construct a currently recognized animal model of lung cancer and to study the synergistic effect of this compound on lung cancer immunotherapy.

[0039] Select 6-8 week old female C57 mice, and after acclimatization, harvest approximately 5 × 10⁸ mice. 5 LLC cells were suspended in 100 μl of serum-free DMEM medium and subcutaneously injected into the right back of mice to construct an LLC lung cancer cell animal model.

[0040] The experiment was divided into five groups: a lung cancer model group, a lung cancer model + low-dose BU intervention group (BU-2.5), a lung cancer model + medium-dose BU intervention group (BU-5), a lung cancer model + high-dose BU intervention group (BU-10), and a lung cancer model + cisplatin positive control group (CDDP). Three doses of BU were dissolved sequentially in solvent systems (5% DMSO, 30% PEG300, 5% Tween 80, and 60% PBS) and administered intraperitoneally. Mice in the model group received a blank solvent system intraperitoneally, while cisplatin in the cisplatin group was dissolved in PBS by sonication. Each mouse in all five groups received 0.1 mL of BU, and the administration period lasted 15 days. Mouse weight and tumor volume were measured every three days using an electronic balance and calipers. After 15 days of administration, animal tissue was collected and weighed, and organ coefficients were calculated.

[0041] In vivo experimental results showed that compound BU could significantly inhibit the progression of lung cancer, and its antitumor effect showed a clear dose-dependent effect.

[0042] By monitoring tumor volume ( Figure 3 ), tumor weight ( Figure 4 and tumor epigenetic changes ( Figure 5 The study found that BU effectively inhibited the growth of lung tumors, with particularly significant tumor-suppressing effects in the high- and medium-dose groups. Notably, compared to the cisplatin-positive control group, which showed a significant decrease in body weight, the body weight of mice in all BU dose groups was not significantly different from that in the model group. Figure 6 The organ coefficient results show () Figure 7The spleen, lung, and thymus indices in the cisplatin group were significantly different from those in the model group, while the organ indices in each BU dose group showed no significant differences compared to the model group. These results fully demonstrate that BU exhibits strong anti-lung cancer activity while also demonstrating good safety, showcasing its promising development potential as an anti-lung cancer drug candidate.

[0043] Example 3: Detection of non-targeted metabolomics samples from tumor samples The steps for tumor tissue sample extraction and testing are as follows, and the information on the reagents and instruments used is shown in Table 1.

[0044] Table 1. Reagent and instrument information for non-targeted metabolomics analysis of tumor samples.

[0045] (1) Remove the tumor sample from the -80 °C freezer and place it on ice to thaw until it can be cut (all subsequent operations are performed on ice); (2) Chop and mix the sample, and weigh 20 mg (±1 mg) from multiple points into the corresponding numbered centrifuge tubes; (3) Add a steel ball with tweezers, homogenize with a ball mill (30 Hz) for 20 s, and centrifuge at 3000 r / min for 30 s at 4 °C to get the sample to the bottom of the tube (the time can be increased appropriately according to the actual homogenization situation). (4) After centrifugation, add 400 μL of 70% methanol-water internal standard extract, shake at 1500 r / min for 5 min, and let stand on ice for 15 min; (5) Centrifuge at 12000 r / min for 10 min at 4 °C, transfer 300 μL of the supernatant to another centrifuge tube with the corresponding number, and let stand in a -20 °C refrigerator for 30 min; (6) Centrifuge at 12000 r / min for 3 min at 4 °C, and transfer 200 μL of the supernatant into the inner tube of the corresponding sample vial for analysis by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0046] Chromatographic conditions: (1) Chromatographic column: Waters ACQUITY Premier HSS T3 Column 1.8 µm, 2.1 mm * 100 mm; (2) Mobile phase A: 0.1% formic acid / water; Mobile phase B: 0.1% formic acid / acetonitrile; (3) Column temperature: 40 °C; flow rate: 0.4 mL / min; injection volume: 4 μL.

[0047] Mass spectrometry conditions are shown in Table 2.

[0048] Table 2. Mass spectrometry conditions for detecting non-targeted metabolomics samples from tumor samples.

[0049] Data preprocessing: Raw mass spectrometry data were converted to mzML format using ProteoWizard. Peak extraction, alignment, and retention time correction were performed using XCMS. Peaks with a missing rate >50% in each sample group were filtered, and blank values ​​were filled using KNN with 1 / 5 minimum value (filling with 1 / 5 minimum value for blank values ​​>50%, and KNN filling for blank values ​​<50%). Peak area was corrected using the SVR method. Metabolite identification was performed on the corrected and filtered peaks by searching the laboratory's self-built database, integrating public libraries, and prediction libraries. Finally, substances with a comprehensive score of 0.5 or higher and a QC sample CV value less than 0.3 were extracted and identified. Positive and negative modes were then merged (retaining the substance with the highest qualitative grade and the smallest CV value), resulting in the all_sample_data.xlsx file.

[0050] Data Analysis: Metabolomics analysis comprises two main parts: metabolomics experiments and data analysis. Data analysis primarily includes screening for differentially expressed metabolites and elucidating metabolic pathways. Based on the metabolomics data obtained through experimental design, sample collection and processing, metabolite extraction, and metabolite detection and analysis, metabolite identification and quality control analysis of sample data can be performed. Differentially expressed metabolites can then be screened, enabling relevant functional predictions and analyses of the sample's metabolites.

[0051] This invention performed metabolomics analysis on tumor samples, and the results of orthogonal partial least squares discriminant analysis (OPLS-DA) further demonstrated significant differences between the model group and the BU-treated group. Figure 8 ); Differential metabolite enrichment analysis (KEGG) results revealed ( Figure 9 The anti-lung cancer effect of TU is mainly related to lipid metabolism pathways. TU can significantly downregulate the levels of lipid components in tumors such as 2E-tetradecenoyl-CoA, LPE (0:0 / 16:1), LPE (0:0 / 16:0), methylcarbamoyl PAF C-16, glycerol-3-phosphate, and chicoryl palmitate. Figure 10 2E-tetradecenoyl-CoA is an important mediator involved in lipid synthesis, and its downregulation directly affects lipid synthesis; therefore, the above results suggest that BU may inhibit lung cancer progression by inhibiting lipid molecule levels in tumors.

[0052] Example 4: Proteomic Detection of Tumor Samples Sample pretreatment: Sample pretreatment included protein extraction, denaturation, reductive alkylation, enzymatic digestion, and peptide desalting. This project used iST sample pretreatment reagents (PreOmics, Germany) for protein pretreatment. An appropriate amount of protein was added to 50 μL of lysis buffer and heated at 95°C and 1000 rpm for 10 min. The sample was cooled to room temperature, and trypsin digestion buffer was added. The mixture was incubated at 37°C and 500 rpm for 2 h with shaking. The enzymatic digestion reaction was terminated by adding stop buffer. Peptide desalting was performed using the iSTcartridge kit, followed by elution with 2 × 100 µL elution buffer. The eluted peptides were vacuum-dried and stored at -80°C.

[0053] DIA Data Acquisition: The desalted lyophilized peptides were reconstituted in phase A (0.1% formic acid aqueous solution) and then analyzed by LC-MS / MS. The entire system was an Orbitrap Astral mass spectrometer (Thermo Fisher Scientific, MA, USA) equipped with FAIMS and a Vanquish NeoUHPLC ultra-high performance liquid chromatography system in series. A total of 200 ng of sample was loaded (AUR3-15075C18 analytical column: 15 cm × 75 μm·d, 1.7 μm particle size, IonOpticks), and the sample was separated by a gradient of 8 min at a column temperature of 50°C. The gradient started with 8% of phase B (80% acetonitrile and 0.1% formic acid), increased to 15% at a flow rate of 700 nL / min over 1 min, increased to 40% at a flow rate of 400 nL / min over 5.5 min, increased to 99% at a flow rate of 700 nL / min over 0.5 min, and maintained at a flow rate of 1000 nL / min for 1 min.

[0054] The mass spectrometer was operated in data-independent acquisition (DIA) mode, and the mass spectrometry parameters were set as follows: (1) Orbitrap: scan range (m / z): 380-980; resolution: 240K; normalized AGC target: 500%; maximum injection time: 3 ms; (2) Astral: Precursor Massrange (m / z): 380-980; normalized AGC target: 500%; maximum injection time: 3ms; collision energy: 25%, isolationWindow: 2m / z, WindowOverlap: 0; loop time: 0.6s. FAIMS CV: -42.

[0055] Database retrieval: DIA data were analyzed using Spectronaut20 with default parameters (BGSFactory Settings (default)). The sequence database was uniprot-Mus musculus (version 2025, 21701 entries), and Trypsin digestion was set. Search parameters were fixed with Carbamidomethylation (C) 57.02 and variable with Oxidation (M) 15.9 and Acetyl (protein N-term) 42.01. The iRT peptide software automatically corrected retention time and quality windows, automatically determining the ideal extraction window. Protein qualitative standards were: Precursor Threshold 1.0% FDR, Peptide Threshold 1.0% FDR, and Protein Threshold 1.0% FDR. The Decoy database was generated using a mutated strategy, similar to shuffling a random number of amino acid sequences (at least 2 amino acids, up to half the total length of the polypeptide). Spectronaut performs automatic correction and employs a local normalization strategy for data normalization. Peptides with a FDR of less than 1.0% are quantified using MaxLFQ for protein group analysis.

[0056] This invention performed proteomic analysis on tumor samples, and the results of differential protein enrichment analysis (KEGG) revealed that ( Figure 11 The anti-lung cancer effect of TU is mainly related to the mTOR signaling pathway. Grb2, a key regulatory target of lipid metabolism, can accelerate tumor progression by promoting lipid accumulation. This study found that TU can significantly downregulate Grb2 protein levels. Figure 12 Therefore, combining tumor metabolomics and proteomics results, BU may inhibit lung cancer progression by blocking lipid metabolism disorders through inhibiting Grb2-mediated lipid over-accumulation. Figure 13 ).

[0057] This invention systematically evaluates the inhibitory effect of ursodeoxycholic acid (BU) on lung cancer progression through in vivo and in vitro experiments. The results show that ursodeoxycholic acid (BU) significantly inhibits the proliferation of various lung cancer cells and the growth of tumors in in vivo lung cancer models, providing a theoretical basis and experimental evidence for developing new strategies for the treatment of lung cancer with BU.

[0058] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. Use of ursodeoxycholic berberine in the preparation of a drug for resisting lung cancer.

2. Use according to claim 1, characterized in that, The lung cancer is specifically non-small cell lung cancer.

3. Use according to claim 1, characterized in that, The ursodeoxycholic berberine can inhibit lung cancer cell proliferation.

4. An anti-lung cancer drug, characterized by, The drug comprises ursodeoxycholic berberine and a pharmaceutically acceptable carrier or excipient.

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