Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.189330.
Abstract
Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in PERK activation in human subjects with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis subjects had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3-/-Lyz2-cre mice was reduced to control levels. PERK increased Atf4 expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a unique therapeutic target to reverse established fibrosis.
Authors
Jyotsana Pandey, Jennifer L. Larson-Casey, Mallikarjun H. Patil, Chao He, Nisarat Pinthong, A. Brent Carter
