Inhibition of ER stress by targeting the IRE1α–TXNDC5 pathway alleviates crystalline silica-induced pulmonary fibrosis

Long-term exposure to crystalline silica (CS) results in silicosis, which is characterized by progressive pulmonary fibrosis. The endoplasmic reticulum (ER) plays a critical role in protein processing, and the accumulation of unfolded proteins triggered by external stimuli often leads to ER stress. In the present study, we found that inhibition of ER stress alleviated CS-induced pulmonary fibrosis. Moreover, we observed that TXNDC5, a resident ER protein, was involved in the activation of fibroblasts. Mechanistically, we explored the relationship between ER stress and TXNDC5 and demonstrated that IRE1α-XBP-1 signaling was closely related to TXNDC5. Pharmacological inhibition of IRE1α endoribonuclease activity, in addition to knockdown of Xbp1 expression, reduced TXNDC5 expression in activated fibroblasts. Furthermore, pharmacological inhibition of IRE1α in vivo ameliorated pulmonary function and delayed CS-induced lung fibrosis. In conclusion, the present study illuminates the role of ER stress-related IRE1α–TXNDC5 signaling in fibroblast activation and its effects on CS-induced pulmonary fibrogenesis, which may provide novel targets for silicosis therapy.