2,3,5,6-Tetrafluoro-4-Methoxy-Benzamide alleviates idiopathic pulmonary fibrosis through activation of LGALS3-mediated AGE-RAGE signaling pathway

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-10-10 DOI:10.1016/j.intimp.2025.115635

Yikun Chen , Qing Liu , Ran Fu , Yucheng Liu , Jiayi Shen , Yi Wang

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引用次数: 0

Abstract

Idiopathic pulmonary fibrosis (IPF), a progressive lung disease with limited therapeutic options, urgently requires novel treatment strategies. This study investigates the mechanism of 2,3,5,6-Tetrafluoro-4-Methoxy-Benzamide (TFMB) in alleviating IPF through LGALS3-mediated AGE-RAGE pathway. Demographic characteristics of IPF patients during 2020–2024 were analyzed. IPF mouse and cell models were induced by bleomycin (BLM) to evaluate the anti-fibrotic effects of TFMB, with validation by LGALS3/RAGE overexpression. Hematoxylin-eosin, Masson's trichrome and Sirius red staining were used to assess inflammatory infiltration and collagen deposition in lung tissues. Western blot, RT-qPCR, biochemical analysis, immunohistochemistry and ELISA were performed for molecular profiling. CCK-8 was employed for cell viability testing. Bioinformatics integration with KEGG/GO analyses were conducted to explore the potential regulatory mechanisms of TFMB. Immunoprecipitation (IP) was utilized to examine the binding between LGALS3 and AGE. Clinical data analysis revealed a progressive decline in the age of IPF patients. TFMB significantly inhibited inflammation infiltration, collagen deposition, and upregulated hydroxyproline content, fibroblast activation-related markers and LGALS3 expression in BLM-challenged mice. In vitro, TFMB suppressed BLM-induced upregulation of CTGF and CX3CL1 mRNA expression, fibroblast activation-related markers, and LGALS3 levels. LGALS3 overexpression abrogated TFMB's therapeutic effect on IPF. KEGG/GO analyses suggested involvement of AGE-RAGE pathway activation in IPF. IP found that LGALS3 bound to AGE, inhibiting AGE-RAGE pathway activation. RAGE overexpression rescued the diminished anti-fibrotic efficacy of TFMB under LGALS3 overexpression. TFMB alleviates IPF by inhibiting LGALS3, thereby suppressing AGE-RAGE signaling pathway activation. TFMB has the potential to be a novel therapeutic drug for IPF.

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2,3,5,6-四氟-4-甲氧基苯甲酰胺通过激活lgals3介导的AGE-RAGE信号通路减轻特发性肺纤维化

特发性肺纤维化（IPF）是一种治疗方案有限的进行性肺部疾病，迫切需要新的治疗策略。本研究探讨了2,3,5,6-四氟-4-甲氧基苯甲酰胺（TFMB）通过lgals3介导的AGE-RAGE通路缓解IPF的机制。分析2020-2024年IPF患者的人口学特征。采用博来霉素（BLM）诱导IPF小鼠和细胞模型，评价TFMB的抗纤维化作用，并通过LGALS3/RAGE过表达验证。采用苏木精-伊红、马松三色、天狼星红染色评价肺组织炎症浸润及胶原沉积。采用Western blot、RT-qPCR、生化分析、免疫组织化学、ELISA等方法进行分子分析。采用CCK-8进行细胞活力检测。结合生物信息学和KEGG/GO分析，探讨TFMB的潜在调控机制。免疫沉淀法（IP）检测LGALS3与AGE的结合。临床数据分析显示，IPF患者的年龄逐渐下降。TFMB显著抑制blm小鼠的炎症浸润、胶原沉积，上调羟脯氨酸含量、成纤维细胞激活相关标志物和LGALS3表达。在体外，TFMB抑制blm诱导的CTGF和CX3CL1 mRNA表达上调、成纤维细胞激活相关标志物上调以及LGALS3水平。LGALS3过表达消除了TFMB对IPF的治疗作用。KEGG/GO分析提示AGE-RAGE通路激活参与IPF。IP发现LGALS3与AGE结合，抑制AGE- rage通路的激活。RAGE过表达挽救了LGALS3过表达时TFMB抗纤维化作用的减弱。TFMB通过抑制LGALS3来缓解IPF，从而抑制AGE-RAGE信号通路的激活。TFMB有潜力成为一种新的治疗IPF的药物。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.