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.
Wei et al. (Mon,) studied this question.
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