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

Our plain-English summary of The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis, by J. Pandey, J.L. Larson-Casey, M.H. Patil, et al (JCI Insight, 2025).

The study

• Authors: J. Pandey, J.L. Larson-Casey, M.H. Patil, C. He, N. Pinthong, A.B. Carter
• Journal: JCI Insight
• Published: 2025;10(10)
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study combined human samples, mouse experiments and cell culture to examine endoplasmic reticulum (ER) stress in lung macrophages during asbestos-induced fibrosis. Lung macrophages collected by bronchoalveolar lavage from people with asbestosis showed increased PERK activation and eIF2alpha phosphorylation that was absent in healthy volunteers, while IRE1alpha phosphorylation was absent in the asbestosis participants; similar PERK activation appeared in macrophages from asbestos-injured mice. Macrophages exposed to asbestos in culture had 25-fold greater PERK phosphorylation than vehicle controls. Mice with macrophage-specific deletion of Eif2ak3 (the PERK gene) were protected from asbestos-induced fibrosis. Macrophages from asbestosis participants showed signs of metabolic reprogramming to fatty acid oxidation, including increased acetyl-CoA, more than a 9-fold increase in isocitrate, and increased CPT1A. ChIP showed ATF4, but not ATF3, bound the Ppargc1a promoter. Giving the PERK inhibitor GSK2656157 from day 13, after fibrosis was established, produced what the authors described as complete resolution of fibrosis in asbestos- and bleomycin-injured mice.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: experimental laboratory study using human bronchoalveolar lavage macrophages, mouse models of asbestos- and bleomycin-induced fibrosis (including conditional knockout mice), and cell-culture experiments
• Who was studied: Lung (BAL) macrophages from healthy volunteers and from people with asbestosis at the University of Alabama at Birmingham; C57BL/6 wild-type, Eif2ak3fl/fl, Eif2ak3-/- Lyz2-cre and Eif2ak3-/- Cx3cr1creER mice; cultured macrophage, alveolar epithelial and fibroblast cell lines
• Exposure: Asbestos (100 micrograms intratracheally in mice) compared with man-made vitreous fiber (MMVF) controls; bleomycin in a second mouse model; asbestos, tunicamycin, thapsigargin or 4PBA in cultured cells; human participants had occupational or environmental asbestos exposure with asbestos bodies in BAL
• Main results:
  • Lung macrophages from humans with asbestosis had increased PERK and eIF2alpha phosphorylation, absent in healthy humans; IRE1alpha phosphorylation was absent in the asbestosis participants
  • In cultured macrophages, asbestos exposure gave 25-fold greater PERK phosphorylation than vehicle control
  • Mice with macrophage-specific Eif2ak3 deletion were protected from asbestos-induced lung fibrosis, whereas Eif2ak3fl/fl mice developed parenchymal fibrosis
  • Lung macrophages from asbestosis participants had increased acetyl-CoA, more than 9-fold increased isocitrate and other TCA metabolites, an increased NAD+-to-NADH ratio, and increased CPT1A
  • Oxygen consumption rate was increased in asbestos-injured Eif2ak3fl/fl mice and decreased in Eif2ak3-/- Lyz2-cre mice
  • ChIP showed ATF4, but not ATF3, bound the Ppargc1a promoter; silencing Atf4 abolished the PERK-driven increase in promoter activity
  • The PERK inhibitor GSK2656157 (30 mg/kg i.p. daily from day 13, after fibrosis was established) was followed by resolution of fibrosis in asbestos-injured mice, confirmed by hydroxyproline assay, with similar results in bleomycin-injured mice
  • Human asbestosis lung macrophages had increased pro-fibrotic gene expression compared with healthy humans
• The authors' conclusion: The authors concluded that PERK activation in lung macrophages drives metabolic reprogramming to fatty acid oxidation via ATF4 and PGC-1alpha, and that PERK is a potential therapeutic target to reverse established pulmonary fibrosis
• Limitations the authors state:
  • The authors did not determine why IRE1alpha is not activated after asbestos exposure
  • Other ER stress-modulated transcription factors besides ATF4 may also regulate Ppargc1a
  • The role of PERK or its inhibition in other cell types involved in fibrosis was not established
  • Translation of the findings to humans with established fibrosis requires further investigation

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Macrophage.

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