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

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.