The Perk/ATF4 Pathway Is Required for Metabolic Reprogramming and Progressive Lung Fibrosis

Authors

Jyotsana Pandey
Jennifer L Larson-Casey
Mallikarjun H Patil
Chao He
Nisarat Pinthong
A Brent Carter

Language

English

Publication Date

5-22-2025

Journal

JCI Insight

DOI

10.1172/jci.insight.189330

PMID

40208691

PMCID

PMC12128959

PubMedCentral® Posted Date

4-10-2025

PubMedCentral® Full Text Version

Post-print

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 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.

Keywords

Animals, eIF-2 Kinase, Activating Transcription Factor 4, Mice, Humans, Pulmonary Fibrosis, Male, Female, Endoplasmic Reticulum Stress, Signal Transduction, Macrophages, Alveolar, Lung, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Disease Models, Animal, Mice, Knockout, Fatty Acids, Mice, Inbred C57BL, Metabolic Reprogramming

Published Open-Access

yes

Recommended Citation

Pandey, Jyotsana; Larson-Casey, Jennifer L; Patil, Mallikarjun H; et al., "The Perk/ATF4 Pathway Is Required for Metabolic Reprogramming and Progressive Lung Fibrosis" (2025). Faculty and Staff Publications. 4763.
https://digitalcommons.library.tmc.edu/baylor_docs/4763