ArticleProceedings of the National Academy of Sciences of the United States of America2022
Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 36 citations in OpenAlex.
- Organelle Crosstalk and Metabolic Reprogramming in Idiopathic Pulmonary Fibrosis: Mechanisms and Therapeutic Implications.Cell biochemistry and function · 2026Review
- Unlocking Alveolar Regeneration: AT2 Stem Cells, Signaling Networks, and Therapeutic Frontiers.Stem cell reviews and reports · 2026Review
- Regulatory T cells protect against aberrant remodeling in a mouse model of pulmonary fibrosis.Mucosal immunology · 2026Article
- Divergent pathways of surfactant protein C maturation for disease-associated isoforms.The Journal of biological chemistry · 2026Article
- Bidirectional fibrogenic cross-talk revealed in a human iPSC-derived epithelial-mesenchymal co-culture model of pulmonary fibrosis.bioRxiv : the preprint server for biology · 2026Article
- From stress to homeostasis: Mass spectrometry-based insights into the unfolded protein response (UPR) and proteostasis.Advances in biological regulation · 2026Review
- Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.The Journal of clinical investigation · 2025Article
- Stress, plasticity, and fibrosis: unfolding the role of the IRE1α/RIDD/Fgfr2 axis.The Journal of clinical investigation · 2025Article
- Divergent Pathways of Surfactant Protein C Maturation for Disease-Associated Isoforms.bioRxiv : the preprint server for biology · 2025Article
- Aberrant intermediate alveolar epithelial cells promote pathogenic activation of lung fibroblasts in preclinical fibrosis models.Nature communications · 2025Article
- Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis.JCI insight · 2025Article
- Emerging Concepts in Therapeutic Interventions for Idiopathic Pulmonary Fibrosis.Seminars in respiratory and critical care medicine · 2025Review
- Mechanisms on How Matricellular Microenvironments Sustain Idiopathic Pulmonary Fibrosis.International journal of molecular sciences · 2025Review
- Consumption of Endogenous Caspase-3 Activates Molecular Theranostic Nanoplatform against Inflammation-Induced Profibrotic Positive Feedback in Pulmonary Fibrosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium.The Journal of clinical investigation · 2025Review
- Pulmonary fibrosis through the prism of NLRP3 inflammasome: mechanistic pathways and prospective therapeutic innovations.Frontiers in immunology · 2025Review
- Alveolar epithelial type 2 cells in acute lung injury and acute respiratory distress syndrome: spatiotemporal fate and regulation.Burns & trauma · 2025Review
- Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome.JCI insight · 2024Article
- Inhibition of IRE1α/XBP1 axis alleviates LPS-induced acute lung injury by suppressing TXNIP/NLRP3 inflammasome activation and ERK/p65 signaling pathway.Respiratory research · 2024Article
- Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration.Nature communications · 2024Article
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
Abstract
Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.