Table of Content

Volume 28 Issue 2
26 February 2023

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Intervention of quercetin in glycolysis of renal interstitial fibroblasts against interstitial fibrosis mechanism

MA Yue, MA Wangbo, ZHOU Zhihua, CHANG Jingwen, FAN Fangtian

2023, 28(2):  121-129.  doi:10.12092/j.issn.1009-2501.2023.02.001

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AIM: To investigate the function and mechanism of quercetin (Que) in anti-fibrosis in vitro and in vivo from the perspective of interfering with the glycolysis of renal interstitial fibroblasts.  METHODS: In vivo experiments, mice were administered in groups, kidneys were dissected, weighed and examined histopathologically and biochemically; In vitro experiments, rat normal renal fibroblasts (NRK-49F cells) were treated with different reagents, proteins were extracted, and NRK-49F cell activation indicators such as α-smooth muscle actin (α-SMA) were detected by protein immunoblotting (Western Blot). The expression of the proteins, such as proliferating cell nuclear antigen (PCNA), was examined by protein immunoblotting (Western Blot), and the effect of Que on glucose uptake in NRK-49F cells induced by transforming growth factor-β (TGF-β1) and epidermal growth factor (EGF) was examined by fluorescence assay; the lactate content of cells in different experimental groups was examined by lactate assay kit; the effect of Que on glucose uptake in NRK-49F cells induced by TGF-β1 and EGF was examined by fluorescence quantitative PCR. EGF-induced mRNA of hexokinase (HK2), phosphofructokinase 1 (PFK1) and muscle pyruvate kinase isozyme 2 (PKM2), key enzymes of glycolysis in NRK-49F cells. RESULTS: Compared with the UUO group, the morphological structures of kidney tissues in the Que administration group were all alleviated to different degrees, which were related to the inhibition of glycolysis, and the serum levels of urea nitrogen (BUN) and blood creatinine (Scr) in mice showed a significant downward trend; lactate production and glucose uptake in NRK-49F cells were gradually reduced, and Que affected TGF-β1 and EGF-induced RIF of mRNA levels of key enzymes of glycolysis gradually decreased and were associated with PKM2. CONCLUSION: Que inhibits PKM2 enzyme activity and glycolysis in NRK-49F cells and reduces TGF-β1-induced myofibroblast activation.

Research on the molecular mechanism of Zuo Jin Wan combined with cetuximab inducing ferroptosis in KRAS mutant colorectal cancer cells

WEI Zhenzhen, SUI Hua, JIANG Yulang, SUN Mingyu, YAN Huaru, WANG Ziyuan

2023, 28(2):  130-137.  doi:10.12092/j.issn.1009-2501.2023.02.002

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AIM: To investigate the mechanism and reversal effect of Zuo Jin Wan (ZJW) on cetuximab (CET) resistance in KRAS mutant colorectal cancer cell.  METHODS: The mutation status of KRAS gene in SW620, Lovo, HCT116, HT29 and Caco2 cells were detected by Sanger sequencing. CCK-8 assay was used to detect the effects of ZJW, CET, ZJW combined with CET and CET, ZJW in combination with other cell death inhibitors on the survival rate of the above cells, and to observe the reversal effects of ZJW on CET-treated KRAS mutant cells (SW620, Lovo and HCT116). Flow cytometry, colorimetric method, and Fe2+ ions fluorescent probe FerroOrange were used to detect the effects of ZJW, CET and their combination on ROS, GSH and Fe2+ levels in KRAS mutant cells. Western blot and real-time PCR were used to detect the regulatory effects of ZJW combined with CET on proteins and mRNA of ferroptosis-related pathway. RESULTS: KRAS mutant cells include HCT116 (KRASG13D), Lovo (KRASG13D) and SW620 (KRASG12V), while HT29 and Caco2 were KRAS wild-type cells. Compared with 125 μg/mL CET-treated KRAS mutant cells, CET at same concentration significantly reduced cell viabilities of KRAS wild-type cells (Caco2 and HT29 cells) by 34.03%and 40.68%, respectively (P<0.01). ZJW (50 μg/mL) combined with CET (125 μg/mL) markedly reduced cell viability of HCT116, Lovo and SW620 cells, which were 59.97%, 59.47%and 52.58%, respectively (P<0.05), compared with the controls. ZJW could enhance ROS and Fe2+ levels, and decrease GSH levels in KRAS mutant cells. When ZJW combined with CET, the effects were more significant (P<0.05，P<0.01). ZJW combined with CET inhibited protein and mRNA expressions of SLC7A11, GPX4, Nrf2 and MDM2 in SW620 cells, and increased the expression of p53 protein. However, the combined treatment did not affect the level of p53 mRNA. CONCLUSION: ZJW could regulate Nrf2 and p53 pathways in KRAS mutant cells, thereby inhibiting SLC7A11 and GPX4 expressions and promoting ferroptosis, which may be the mechanism of reversing CET resisgtance.

Mechanisms of Radix Tetrastigma on anti rheumatoid arthritis via regulating the balance of Th17/Treg

WANG Tiefeng, SU Jie, WANG Weidong, XIA Rongshuang, LI Sifan, ZHU Wenrui, LOU Zhaohuan

2023, 28(2):  138-146.  doi:10.12092/j.issn.1009-2501.2023.02.003

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AIM: To explore the possible mechanism of Radix Tetrastigma (RT) on anti-rheumatoid arthritis (RA).  METHODS: The rat model of RA was established by intradermal injection of complete Freund's adjuvant into the right hind foot of SD rats. RT Extract with different dosage was continuous intragastric administration for 3 weeks, then, the degree of foot swelling, arthritis index score, joint heat and grip of each rat was measured respectively. ELISA was used to detect the expression levels of Interleukin (IL) 6, IL-17, IL-10, tumor necrosis factor-α, and rheumatoid factor. Fully automatic hemorheometer was applied to measure hemorheology indexes. The number of CD4+IL-17+T cells and CD4+CD25+Foxp3+T cells in peripheral blood were measured by flow cytometry. HE staining was used to observe the pathological changes of ankle joints. Western blot was used to measure expressions of IL-6, RORγt, Foxp3, STAT3 and p-STAT3 proteins in synovial tissues of joints. RESULTS: RT could significantly decrease swelling degree, arthritis index scores and joint heat of rats with RA. Grasping power of rats was improved and the serum levels of IL-6, IL-17, TNF-α and RF were significantly decreased, levels of IL-10 was increased significantly. Th17/Treg ratio in whole blood was decreased. Protein expressions of IL-6, STAT3, p-STAT3, and RORγt were down-regulated and Foxp3 protein was up-regulated in synovial tissues of joints. Functional morphology of the ankle joint of the plantar of rats with RA were significantly improved. CONCLUSION: RT has obvious anti-rheumatoid arthritis effect, and its mechanism may be related to regulating Th17/Treg balance by regulating IL-6/STAT3 axis.

Network analysis and experimental verification of  Schisandrin B reduces intestinal ischemia reperfusion injury

HOU Xiaoyu, LENG Yufang, CAO Xuefen, LV Xingjiao, HAN Xiaoxia, Janvier NIBARUTA, LIU Yongqiang

2023, 28(2):  147-154.  doi:10.12092/j.issn.1009-2501.2023.02.004

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AIM: To explore schisandrin B (Sch B) pretreatment reduces intestinal ischemia reperfusion injury (IIRI) through inhibiting apoptosis by activation of Nrf2/HO-1 signing pathway in mice by network pharmacology and in vivo experiment.  METHODS: (1) The targets of Sch B and IIRI were searched from online databases, Drawing Venn diagram to obtain the common target of them. Cytoscape software was imported to construct the protein-protein interaction (PPI) network to establish the "Drugs-Disease-core target gene" network. The mechanism of Sch B against IIRI was predicted through GO and KEGG enrichment analysis. (2) Thirty-six C57BL/6J mice were randomly divided into six groups (n=6). The model of IIRI was established in four groups except the sham operation group. Three of the groups were pretreated with Sch B, Nrf2 inhibitor ML385, and Sch B+ML385, respectively. After the experiment, intestinal tissue samples were taken for HE staining, Chiu's score, apoptosis staining, immunohistochemistry (IHC), and immunoblotting (Western blot). RESULTS: A total of 412 Sch B related targets, 2 166 IIRI related targets and 153 common targets were screened out through network pharmacology. There were 88 "Sch B-IIRI-core target gene" included NFE2L2 (Nrf2), HMOX1 (HO-1), BCL2, CASP3 (caspase 3), and so on. KEGG enrichment analysis screened 163 related pathways, apoptosis pathway ranked  high showing that the pathway may play a key role in the treatment of IIRI by Sch B. The animal experiment had shown that Sch B reduced the Chiu's score and apoptotic while upregulating Nrf2, HO-1, Bcl-2 protein expression levels and Bcl-2/Bax, downregulating Bax, and cleaved caspase-3 expression levels, thereby reducing IIRI in mice, and that Nrf2 inhibitor ML385 reversed this process (P<0.05). CONCLUSION: This study reveals that Sch B has the characteristics of multi-target and multi-pathway in the reduction of IIRI, and Sch B can reduce IIRI through inhibiting apoptosis by activation of Nrf2/HO-1 pathway.

Mechanism of gambogenic acid inhibiting the proliferation of melanoma based on RNA-seq sequencing technology

LIU Chun, WANG Meng, CHENG Hui, LI Qinglin

2023, 28(2):  155-163.  doi:10.12092/j.issn.1009-2501.2023.02.005

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AIM: By analyzing the effect of gambogenic acid (GNA) on the mRNA expression profile of melanoma xenograft model mice, the possible mechanism of GNA in the treatment of melanoma was explored.  METHODS: The inhibitory effect of GNA on melanoma cells was studied by measuring the cell survival rate by MTT method in vitro and observing the cell morphology under an inverted microscope. In the in vivo experiment, the effect of GNA on the growth of xenografted tumors in melanoma mice was observed by comparing the results of HE (hematoxylin-eosin) staining and immunohistochemistry (Ki-67), and the tumor weight and tumor weight ratio were recorded. RNA-seq sequencing technology was used to sequence the GNA medium-dose group and the model group, and the screened mRNAs were analyzed by GO and KEGG, and finally the screening results of differentially expressed genes were verified by real-time quantitative fluorescent PCR. RESULTS: After different doses of GNA acted on the melanoma mouse model, a large area of necrosis occurred in the tumor tissue of the model mouse, and the tumor growth was significantly inhibited. A total of 36 differentially expressed mRNAs were identified by mRNA sequencing, of which 30 were up-regulated and 6 were down-regulated. The possible functions of the mRNAs were predicted according to the genomic adjacency analyzed by GO and KEGG. The expression of the selected differential mRNAs was further verified by real-time quantitative PCR technology. The results showed that the mRNA expressions of Cidec, Ces1d, Mylk4, and Igkv9-123 were up-regulated, and the mRNA expressions of Ryr3 and Hapln1 were down-regulated. CONCLUSION: GNA can inhibit the proliferation of melanoma cells in vitro and in vivo, and its mechanism is related to the regulation of cytokine-cytokine receptor interaction, NF-κB, MAPK, and other pathways of mRNA expression.

Silencing ZKSCAN3 gene expression aggravates lung injury induced by LPS in mice

ZHANG Lei, XIAO Xingpeng, DING Huang

2023, 28(2):  164-170.  doi:10.12092/j.issn.1009-2501.2023.02.006

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AIM: To explore the role of ZKSCAN3 in acute lung injury (ALI) induced by lipopolysaccharide (LPS).  METHODS: After verifying the efficacy of ZKSCAN3 siRNA, male C57BL/6 mice were randomly divided into 4 groups (n=8): control group(group A), LPS group (group B), scrambled siRNA group (group C) and ZKSCAN3 siRNA group (group D). Mice in groups A and B were given 1 mL of PBS via tail vein; mice in groups C were given corresponding doses of PBS containing scrambled siRNA; and mice in group D were given corresponding doses of RNase-free PBS containing ZKSCAN3 siRNA (50 μg) . After 24 hours, mice in groups B, C, and D were instilled with LPS solution (5 mg/kg) through tracheal intubation to create an ALI model; group A was given the corresponding dose of PBS (20 μL). The samples were collected and tested 24 hours after the modeling administration. RESULTS: Compared with group B, silencing ZKSCAN3 gene expression reduced SOD activity and Bcl-2 level; while MDA, Bax and caspase-3 increased; correspondingly, the content of protein and cells in BAL, the apoptosis rate of lung tissue and the pathological score significantly increased (P<0.05).CONCLUSION: Silencing ZKSCAN3 gene expression aggravates the lung injury caused by LPS, which may aggravate the pathological damage of lung tissue in mice by weakening the antioxidant function and aggravating tissue necrosis.

Bioequivalence study of cinacalcet hydrochloride tablets in healthy Chinese volunteers

YAN Qiangyong, XIANG Daxiong, ZHU Ronghua, YANG Lingfeng, YANG Xiding, LI Jingjing, FAN Xiao, LIU Sai, XIONG Shoujun, FANG Pingfei

2023, 28(2):  171-177.  doi:10.12092/j.issn.1009-2501.2023.02.007

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AIM: To evaluate the bioequivalence of cinacalcet hydrochloride tablets in healthy Chinese volunteers. METHODS: A randomized, open, double-period and crossover trial was conducted, 48 healthy volunteers were administered a single dose of cinacalcet test tablets or reference tablets orally under each fasting and fed condition. The concentration of cinacalcet was determined by validated LC-MS/MS method. Pharmacokinetic parameters were calculated by Phoenix WinNonlin 8.0 to study its bioequivalence. RESULTS: The main pharmacokinetic parameters of test tablets and reference tablets under fasting condition were as follows: Cmax (5.96±4.15) and (6.11±4.08) ng/mL, AUC0-72h (45.82±30.20) and (46.11±29.50) ng·h·mL-1, AUC0-∞  (49.65±33.64) and (49.63±32.01) ng·h·mL-1, Tmax (4.5［1.0, 6.0］) and (4.5［1.0, 6.0］) h, t1/2 (23.15±9.23) and (22.43±8.81) h, respectively. Under fed condition, the main pharmacokinetic parameters of test tablets and reference tablets were as follows: Cmax (11.14±5.24) and  (10.24±5.39) ng/mL, AUC0-72h (76.70±39.34) and (75.18±34.36) ng·h·mL-1, AUC0-∞ (83.28±43.00) and (81.38±38.03) ng·h·mL-1, Tmax (3.0［1.5,5.0］) and (4.3［1.5,7.0］) h, t1/2 (28.07±6.37) and (27.46±5.44) h, respectively. The 90%confidence intervals of the geometric average ratios of Cmax, AUC0-72h and AUC0-∞ were all within the equivalent interval of 80.00%-125.00%. CONCLUSION: Two formulations of cinacalcet tablets are bioequivalent and safe.

Effect of iron dextran dispersible tablets on heart failure patients with iron deficiency

PENG Yong, FAN Jianfeng, XIONG Xuhua, XIAO Dongping, GAO Zhaobo, ZHENG Chunhua

2023, 28(2):  178-183.  doi:10.12092/j.issn.1009-2501.2023.02.008

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AIM: To evaluate the clinical effect of Iron Dextran Dispersible Tablets on patients with chronic heart failure who reduced ejection fraction after 24 weeks. METHODS: From January 2020 to June 2022, forty-five patients with heart failure complicated with iron deficiency and reduced ejection fraction were selected as the research objects. According to the random number table, they were randomly divided into control group and observation group.The control group was given routine anti-heart failure treatment such as Sacubitril Valsartan sodium tablets, while the observation group was given iron dextran dispersible tablets 50 mg three times a day on the basis of the anti-heart failure treatment of the control group for 8 weeks. The 6-minute walking distance, Hemoglobin, Serum Ferritin, N-terminal B-type natriuretic peptide precursor, Left Ventricular Ejection Fraction, Left Ventricular end Diastolic Diameter and 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) overall summary score and clinical summary score were compared between the two groups.RESULTS: There was no significant difference in baseline data between the two groups (P>0.05). After treatment, the 6-minute walking distance in the observation group was longer than that in the control group, while the serum ferritin level in the observation group was higher than that in the control group. The N-terminal pro-B-type natriuretic peptide level in the two groups was lower than that before treatment, and the left ventricular end diastolic diameter was shorter than that before treatment, and the left ventricular ejection fraction, clinical comprehensive score and symptom score were higher than that before treatment. The difference was statistically significant (P<0.05). There was no significant difference in the total incidence of adverse reactions between the two groups (P>0.05). CONCLUSION: Iron Dextran Dispersible Tablets can improve the exercise endurance and quality of life of patients with chronic heart failure who reduced ejection fraction after 24 weeks.

Exploring the outbreak point for clinical pharmacists to provide pharmaceutical care in nephrology department

ZHANG Zhaowei, LI Zuojun, HUANG Jian, LI Shuangqing, HE YiLin

2023, 28(2):  184-188.  doi:10.12092/j.issn.1009-2501.2023.02.009

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AIM: To introduce the entry point of clinical pharmacists on developing pharmaceutical care in the department of nephrology to further explore more pharmaceutical care entry point and to better promote rational drug use.  METHODS: To summarize the work of the clinical pharmacists participate in the formulation and optimization of anti-infection therapy; participate in the formulation of parenteral nutrition program; conduct medication and adherence education; conduct pharmaceutical monitoring; provide evidence-based medical analysis for the off-label drug use in the department of nephrology by case sharing. RESULTS: Clinical pharmacists provide pharmaceutical care in the department of nephrology. This improves the medication compliance, avoids adverse reactions, optimize therapeutic regimen.CONCLUSION: Developing various pharmaceutical care in the department of nephrology will be safe, effective and economic for drug application.

State of clinical application of meloxicam

LI Xinyu, HUANG Xin

2023, 28(2):  189-197.  doi:10.12092/j.issn.1009-2501.2023.02.010

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Meloxicam is a long-acting non-steroidal anti-inflammatory drug, which is mainly used in the treatment of chronic osteoarthritis and postoperative analgesia. Recent studies have found that the drug has great therapeutic potential in anti-tumor, improving cognitive impairment in Alzheimer's disease, mobilizing hematopoietic stem cells and so on. This paper reviewed the pharmacological mechanism of meloxicam, the adverse reactions in gastrointestinal tract, kidney, liver and cardiovascular aspects, summarized various forms of clinical application from the perspective of preparation, and summarized the current clinical treatment strategy of combining with Western medicine and Chinese medicine respectively.

Pharmacotherapy of patients with left ventricular assist devices

YU Yahong, SONG Yu

2023, 28(2):  198-204.  doi:10.12092/j.issn.1009-2501.2023.02.011

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Left ventricular assist devices (LVAD) are increasingly used in patients with end-stage heart failure. Devices significantly affect patient physiology, leading to unique complications and different drug treatment strategies. The pharmacist is an integral part of a multidisciplinary team and has the responsibility to help patients use their medicines safely and appropriately. It is important to anticipate common postoperative complications and prepare appropriate treatments for them. This article reviews the current guidelines and research literature on the management of pharmacotherapy in patients with LVAD, integrates clinical research practice, summarizes the medication relevant experience and presents a review. 

Clinical research progress of palbociclib in treatment of breast cancer

WANG Zhi, ZHOU Xin, HE Xueru, FU Yuhao, XUN Xuejiao, LI Ying, DONG Zhanjun

2023, 28(2):  205-213.  doi:10.12092/j.issn.1009-2501.2023.02.012

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Palbocicril, the first cyclin-dependent kinases 4 and 6 inhibitors, is a crucial milestone in the development history of antineoplastic drugs. It combined with aromatase inhibitor or fulvestrant as first-line, second-line or post-line therapy has good efficacy and safety for hormone receptor-positive, human epidermal growth factor receptor-2 negative locally advanced or metastatic breast cancer, which has a good application prospect. This article summarizes the clinical trials and safety studies related to palbociclib.

Study on the effect of vitamin D on diabetic neuropathy through mitochondrial/autophagy pathway

BAI Jia, YANG Hong, LI Lingling, ZHANG Yangyang, YANG Ying, LV Haihong

2023, 28(2):  214-219.  doi:10.12092/j.issn.1009-2501.2023.02.013

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The main function of vitamin D is to regulate calcium homeostasis and bone metabolism, but in recent years, it has also been confirmed that it can participate in mitochondrial metabolism and autophagy, and further affect skeletal muscle cells, liver cells, nerve cells, etc. This article mainly discusses the effect of vitamin D on diabetic neuropathy by improving mitochondrial function and regulating autophagy, so as to provide a theoretical basis for the clinical application of vitamin D.

Tirzepatide: A new glucagon-like peptide-1 receptor/glucose-dependent insulinotropic peptide receptor dual agonist

ZHAO Shifeng, SONG Xiangming, YAO Jianping

2023, 28(2):  220-227.  doi:10.12092/j.issn.1009-2501.2023.02.014

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Tirzepatide is the first-in-class dual agonist of glucagon-like peptide-1 (GLP-1) receptor  and glucose-dependent insulinotropic peptide (GIP) receptor, which plays a variety of physiological effects by imitating natural GLP-1 and GIP. In the completed large phase Ⅲ series of clinical studies of SURPASS and SURMOUNT, Tirzepatide has demonstrated excellent effects in decreasing glycosylated hemoglobin, reducing weight, improving blood lipid and other metabolic indicators, and is superior to the currently approved GLP-1 receptor agonist. Gastrointestinal reaction is the most common adverse event of the drug, which is generally mild to moderate, and decreases with continuous administration. On May 13, 2022, Tirzepatide was approved for listing by FDA, the current indication is to improve glycemic control of adult patients with type 2 diabetes (T2D) as an adjunct of diet and exercise. In addition to T2D and obesity, there are also extensive and in-depth studies on other metabolic fields. This paper makes a systematic overview of this.

Helicobacter pylori infection influences the efficacy of immunotherapies for gastric cancer#br#

WANG Dan, YAN Xiaoli, ZHANG Yuan

2023, 28(2):  228-234.  doi:10.12092/j.issn.1009-2501.2023.02.015

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Gastric cancer is a common malignant tumor of digestive tract, and its incidence rate and mortality are very high in China. In recent years, immunotherapy represented by immunocheckpoint inhibitors has brought new therapeutic hope for patients with inoperable advanced gastric cancer. Helicobacter pylori infection is closely related to the occurrence and development of gastric cancer. In this review, we summarized the current status of immunotherapy for gastric cancer, the latest research progress on the impact of Helicobacter pylori infection on gastric mucosal immunity and tumor immunotherapy, and summarized the current challenges and future research directions, with a view to providing new ideas for clinical therapy and scientific research.

Research progress of metformin in the pathogenesis of pulmonary fibrosis

WANG Jie, LI Long, CHEN Feng, LIU Shengfei

2023, 28(2):  235-240.  doi:10.12092/j.issn.1009-2501.2023.02.016

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Pulmonary fibrosis is a chronic, progressive and irreversible respiratory disease characterized by hyperposition of extracellular matrix leading to inflammation and extensive lung remodeling. There is currently no effective treatment. Multiple studies have shown that metformin is a classic antiglycemic drug with antifibrotic potential. However, at present, there is no consensus on the specific mechanism of metformin's anti-fibrosis effect, and this paper reviews the research progress of metformin in the field of pulmonary fibrosis in recent years, mainly from IGF-1/IGF-1R/PI3K signaling, AMPK/mTOR signaling, TGF-β/Smad signaling pathway, and intervening in myofibroblast proliferation and apoptosis, improving oxidative stress, inhibiting epithelial interstitial transformation and transglutaminase. In order to be able to more deeply and comprehensively understand the antifibrosis mechanism and clinical application scope of metformin in the future, and provide new ideas for the treatment of pulmonary fibrosis.