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  3. Combatting Silicosis Fibrosis: Methyl Gallate Suppresses Pathogenic Fibroblasts Through hnRNPA2/B1-MDM4-P53 Network Disruption

Combatting Silicosis Fibrosis: Methyl Gallate Suppresses Pathogenic Fibroblasts Through hnRNPA2/B1-MDM4-P53 Network Disruption

  • FASEB J. 2026 Jan 31;40(2):e71446. doi: 10.1096/fj.202502303RR.
Y Wei 1 2,  Y J Wu 1 2,  W R He 1 2,  P Zhao 1 2 3,  Q Zhang 1 2 3,  J S Li 1 2 3 4
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
  • 2 Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed by Henan Province & Education Ministry of P.R. China, Zhengzhou, Henan, China.
  • 3 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China.
  • 4 Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
PMID: 41524611 DOI: 10.1096/fj.202502303RR
Abstract

Silicosis, an occupational pulmonary fibrosis caused by silica dust exposure, lacks effective treatments. This study investigates the therapeutic potential and mechanism of methyl gallate (MG), a natural polyphenol, in silicosis fibrosis. A silica-induced silicosis mouse model and TGF-β1-stimulated human lung fibroblasts were employed. MG administration significantly ameliorated lung fibrosis in mice, reducing Collagen deposition, α-SMA, fibronectin, and TGF-β1 levels. Transcriptomic analysis revealed that MG inhibited fibroblast activation by suppressing cell cycle progression via CDK6-mediated G0/G1 arrest. Mechanistically, MG downregulated MDM4 protein levels, disrupted MDM4-P53 interaction, and activated the P53-P21 pathway, promoting fibroblast Apoptosis and cell cycle arrest. Further, Drug Affinity Responsive Target Stability (DARTS) and Cellular Thermal Shift Assay (CETSA) identified hnRNPA2/B1 as MG's direct target. MG inhibited hnRNPA2/B1-mediated MDM4 mRNA translation, thereby reducing MDM4 protein synthesis. Overexpression of MDM4 or knockdown of hnRNPA2/B1 reversed MG's anti-fibrotic effects. These findings highlight MG's novel role in alleviating silicosis fibrosis by targeting the hnRNPA2/B1-MDM4-P53 axis, offering a promising therapeutic strategy for silicosis.

Keywords

MDM4; fibroblasts; hnRNPA2/B1; methyl gallate; silicosis.

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