TRIM2 exacerbates the advancement of idiopathic pulmonary fibrosis by modulating β-catenin and endoplasmic reticulum stress.

BACKGROUND: The progression of idiopathic pulmonary fibrosis (IPF) is closely associated with endoplasmic reticulum stress (ERS). However, its precise regulatory mechanism has not been fully elucidated. As an E3 ubiquitin ligase, the biological function of TRIM2 in IPF and its regulatory role in ERS remain unexplored. METHODS: We analyzed the transcriptomic data of IPF from the Gene Expression Omnibus (GEO) database and collected clinical lung tissue samples. The expression of TRIM2 was detected using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry (IHC). An in vitro pulmonary fibrosis model was established by treating A549 cells with 10 ng/mL TGF-β1 for 48 h. Based on this model, short hairpin RNA (shRNA) was used to knock down TRIM2 expression. Cell Counting Kit-8 (CCK-8) and scratch assay were employed to evaluate cell proliferation and migration abilities. Additionally, Western blot was performed to analyze the expression changes of epithelial-mesenchymal transition (EMT) markers (E-cadherin, α-SMA, Collagen I), endoplasmic reticulum stress (ERS)-related proteins (p-IRE1, IRE1, ATF6, GRP78), and β-catenin. RESULTS: This study demonstrated that TRIM2 was significantly upregulated in both IPF patients' lung tissues and TGF-β1-induced A549 cells. Functional experiments revealed that TRIM2 knockdown markedly suppressed TGF-β1-induced cell proliferation and migration, while reversing the epithelial-mesenchymal transition process-evidenced by increased E-cadherin and decreased α-SMA and Collagen I expression. Mechanistic investigations showed that TRIM2 knockdown effectively inhibited endoplasmic reticulum stress, as indicated by reduced expression of key ERS markers including p-IRE1, IRE1, ATF6, and GRP78. Notably, the ERS inducer thapsigargin reversed the suppressive effects of TRIM2 knockdown on cell proliferation, migration, EMT, and ERS. Furthermore, we discovered, for the first time, that TRIM2 negatively regulates β-catenin expression, and the β-catenin inhibitor JW55 partially restored the fibrotic phenotypes suppressed by TRIM2 knockdown. CONCLUSION: This study demonstrates that TRIM2 promotes idiopathic pulmonary fibrosis progression by regulating β-catenin expression and endoplasmic reticulum stress, providing new insights into IPF pathogenesis.