The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis

• Published in: JCI insight Vol. 10; no. 10
• Main Authors: Pandey, Jyotsana, Larson-Casey, Jennifer L., Patil, Mallikarjun H., He, Chao, Pinthong, Nisarat, Carter, A. Brent
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 22.05.2025
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Animals; Disease Models, Animal; eIF-2 Kinase - antagonists & inhibitors; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Stress; Fatty Acids - metabolism; Female; Humans; Lung - metabolism; Lung - pathology; Macrophages, Alveolar - metabolism; Male; Metabolic Reprogramming; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Signal Transduction; Fatty acid oxidation; Pulmonology; Immunology; Macrophages; Fibrosis
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.189330

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 protein kinase RNA-like ER kinase (PERK; Eif2ak3) activation in humans 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 individuals 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 activating transcription factor 4 (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 therapeutic target to reverse established fibrosis.