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Background: 4-phenylbutyric acid (4-PBA) is a chemical chaperone that may aid the folding of proteins and alleviate endoplasmic reticulum (ER) stress by inhibiting the unfolded protein response (UPR). This study explores the effects of 4-PBA on idiopathic pulmonary fibrosis (IPF) using a murine model of bleomycin (BLM)-induced pulmonary fibrosis.Methods: Pulmonary fibrosis was induced in C57BL/6 mice by intratracheal injection of BLM. Sixty mice were randomly allocated into three groups: BLM group (n=20), BLM+4-PBA group (n=20), and control group (n=20). Lung tissues and lung function were analyzed to evaluate the degree of pulmonary fibrosis and the survival of the mice was noted. The expression levels of the ER stress markers activating transcription factor 6 (ATF6) and C/EBP Homologous Protein (CHOP) were analyzed in lung tissues from IPF patients and healthy controls as well as the mice.Results: Lung tissues from IPF patients expressed significantly higher levels of ATF6 and CHOP compared to those from healthy controls. BLM induced significant collagen deposition in the lungs of the mice, which was prevented by 4-PBA. 4-PBA also dramatically improved pulmonary function and increased the survival rate in the BLM+4-PBA group compared to that in the BLM group. Both the protein and mRNA expression levels of ATF6 and CHOP were significantly reduced in mouse lung tissue after 2 weeks of 4-PBA treatment.Conclusions: This study demonstrated that 4-PBA treatment could alleviate BLM-induced pulmonary fibrosis in mice via the attenuation of ER stress.