Mapping fibroblast plasticity across non-cancer lung diseases at single-cell resolution.
4 affiliations
- 1Guangzhou National Laboratory, Guangzhou, 510320, China.
- 2Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
- 3Guangzhou National Laboratory, Guangzhou, 510320, China. [email protected].
- 4Guangzhou National Laboratory, Guangzhou, 510320, China. [email protected].
Abstract
Background
Fibroblast plasticity underlies a wide spectrum of pulmonary diseases, yet the molecular programs governing fibroblast state transitions in non-malignant contexts remain poorly understood.Methods
We integrated 1,470,730 single-cell transcriptomes across three non-cancer lung diseases to construct a comprehensive fibroblast atlas. Integrated clustering and regulon analyses were used to delineate fibroblast subtypes, disease-associated transcriptional programs, and state transitions. ANTXR1, identified as a representative regulator, was validated by tissue immunohistochemistry and siRNA knockdown in primary lung fibroblasts under TGF-β stimulation.Results
Compared with malignancy, fibroblasts in non-cancer lungs exhibited relatively modest transcriptional alterations but maintained distinct disease-associated phenotypes. We further identified a set of fibroblast-specific genes unique to non-malignant contexts, defining molecular features that distinguish fibrotic remodeling from tumor-associated stromal activation. Analysis of fibroblast subtype- and disease-specific regulons revealed 76 gene signatures that were significantly inversely correlated with lung function and distinguished chronic from acute fibrotic fibroblast states. Functional validation demonstrated that ANTXR1 knockdown markedly reduced COL1A1 expression, underscoring its role in fibroblast activation.Conclusions
This work establishes a comprehensive single-cell fibroblast atlas of non-cancer lung diseases, uncovering disease- and subtype-specific regulatory programs and highlighting potential therapeutic targets for fibrotic remodeling.
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BibTeX
@article{yang2026mapping,
title = {{Mapping fibroblast plasticity across non-cancer lung diseases at single-cell resolution.}},
author = {Junhui Yang and Xin Zhang and Minghui Tang and Yuanpei Jiang and Zhiying Chen and Cuinan Lai and Jingyi Bao and Jin Su and Dan Cui and Jia Li},
journal = {Genome medicine},
year = {2026},
month = jul,
doi = {10.1186/s13073-026-01730-x},
url = {https://europepmc.org/article/MED/42897601},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Mapping fibroblast plasticity across non-cancer lung diseases at single-cell resolution.
AU - Junhui Yang
AU - Xin Zhang
AU - Minghui Tang
AU - Yuanpei Jiang
AU - Zhiying Chen
AU - Cuinan Lai
AU - Jingyi Bao
AU - Jin Su
AU - Dan Cui
AU - Jia Li
PY - 2026
DA - 2026/07/01
JO - Genome medicine
DO - 10.1186/s13073-026-01730-x
UR - https://europepmc.org/article/MED/42897601
AB - Background Fibroblast plasticity underlies a wide spectrum of pulmonary diseases, yet the molecular programs governing fibroblast state transitions in non-malignant contexts remain poorly understood.Methods We integrated 1,470,730 single-cell transcriptomes across three non-cancer lung diseases to construct a comprehensive fibroblast atlas. Integrated clustering and regulon analyses were used to delineate fibroblast subtypes, disease-associated transcriptional programs, and state transitions. ANTXR1, identified as a representative regulator, was validated by tissue immunohistochemistry and siRNA knockdown in primary lung fibroblasts under TGF-β stimulation.Results Compared with malignancy, fibroblasts in non-cancer lungs exhibited relatively modest transcriptional alterations but maintained distinct disease-associated phenotypes. We further identified a set of fibroblast-specific genes unique to non-malignant contexts, defining molecular features that distinguish fibrotic remodeling from tumor-associated stromal activation. Analysis of fibroblast subtype- and disease-specific regulons revealed 76 gene signatures that were significantly inversely correlated with lung function and distinguished chronic from acute fibrotic fibroblast states. Functional validation demonstrated that ANTXR1 knockdown markedly reduced COL1A1 expression, underscoring its role in fibroblast activation.Conclusions This work establishes a comprehensive single-cell fibroblast atlas of non-cancer lung diseases, uncovering disease- and subtype-specific regulatory programs and highlighting potential therapeutic targets for fibrotic remodeling.
SN - 1756-994X
ER -