EPDR1 Links Fibroblast Dysfunction to Disease Severity in Idiopathic Pulmonary Fibrosis

초록

Highlights What are the main findings? EPDR1 is significantly upregulated in IPF lung fibroblasts, tissues, BALF, and serum, and it is associated with poor prognosis. EPDR1 knockdown restores lysosomal acidification, improves autophagic flux, and reduces cellular senescence in IPF fibroblasts. What is the implication of the main finding? EPDR1 contributes to lysosomal dysfunction and fibroblast senescence, which are key pathogenic features of IPF. EPDR1 may serve as a novel biomarker and potential therapeutic target in idiopathic pulmonary fibrosis.Highlights What are the main findings? EPDR1 is significantly upregulated in IPF lung fibroblasts, tissues, BALF, and serum, and it is associated with poor prognosis. EPDR1 knockdown restores lysosomal acidification, improves autophagic flux, and reduces cellular senescence in IPF fibroblasts. What is the implication of the main finding? EPDR1 contributes to lysosomal dysfunction and fibroblast senescence, which are key pathogenic features of IPF. EPDR1 may serve as a novel biomarker and potential therapeutic target in idiopathic pulmonary fibrosis.Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by aberrant fibroblast activation, lysosomal dysfunction, and cellular senescence. Transcriptomic analyses have identified ependymin-related 1 (EPDR1) as a fibroblast-enriched gene in IPF, but its biological function remains unclear. EPDR1 expression was assessed in lung fibroblasts, lung tissues, bronchoalveolar lavage fluid (BALF), and serum from IPF patients and controls using qPCR, Western blotting, ELISA, and immunohistochemistry. Lysosomal function, autophagic flux, and senescence markers were analyzed in primary fibroblasts following siRNA-mediated EPDR1 knockdown. EPDR1 was significantly upregulated in IPF-derived fibroblasts and localized to fibrotic regions enriched with alpha-SMA+, COL1A1+, and FN1+ myofibroblasts of IPF-derived lung tissues. EPDR1 levels were markedly elevated in the BALF and serum of IPF patients and correlated with increased mortality. IPF fibroblasts exhibited reduced lysosomal acidification and impaired autophagic flux, indicated by p62 and LC3B accumulation. EPDR1 knockdown restored lysosomal function; enhanced autophagic degradation; and reduced senescence markers, including p21, p16, and SA-beta-gal activity. EPDR1 drives lysosomal dysfunction and fibroblast senescence in IPF. Its elevated expression in lung tissue and biological fluids, together with its association with prognosis, highlights EPDR1 as a potential biomarker and therapeutic target in IPF.

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