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

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

  • Int Immunopharmacol. 2025 Oct 10:167:115635. doi: 10.1016/j.intimp.2025.115635.
Yikun Chen 1,  Qing Liu 2,  Ran Fu 3,  Yucheng Liu 2,  Jiayi Shen 2,  Yi Wang 4
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
  • 2 Jiangsu University, Zhenjiang 212013, China.
  • 3 Department of Pulmonary and Critical Care Medicine, The Second People's Hospital of Huai'an, the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an 223000, China.
  • 4 Department of Pulmonary and Critical Care Medicine, The Second People's Hospital of Huai'an, the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an 223000, China. Electronic address: 13515242788@163.com.
PMID: 41075750 DOI: 10.1016/j.intimp.2025.115635
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.

Keywords

2,3,5,6-Tetrafluoro-4-Methoxy-Benzamide; AGE-RAGE; Extracellular matrix remodeling; Idiopathic pulmonary fibrosis; LGALS3.

Figures
Products