RUNX1 links ATF4-associated stress adaptation to microenvironmental remodeling in POSTN+ fibroblasts during skin fibrosis.
- 1Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, No. 127 Changle West Road, Xincheng District, Xi'an 710032, Shaanxi Province, People's Republic of China.
Abstract
Background
Skin fibrosis encompasses a spectrum of disorders and includes hypertrophic scar (HTS), keloid scar (KS), and systemic sclerosis (SSc), but the pathogenic fibroblast states and shared upstream regulators contributing to these conditions remain incompletely defined. As a common form of skin fibrosis, HTS provides a useful model for elucidating fibroblast heterogeneity and mechanism-based therapeutic vulnerability across skin fibrosis diseases. This study aimed to define the role of RUNX1 in pathogenic POSTN+ fibroblasts during skin fibrosis and to investigate the underlying stress-adaptive and microenvironment-remodeling mechanisms.Methods
We performed single-cell RNA sequencing, spatial transcriptomic analysis, multiomics profiling, and cell-cell communication analysis to identify pathogenic fibroblast subpopulations and their regulatory networks in HTS. RUNX1-centered mechanisms were analyzed by CUT&Tag, RNA sequencing, rescue experiments, and functional assays, followed by in vitro and in vivo validation. High-throughput virtual screening and structural analyses were used to computationally prioritize candidate compounds predicted to bind to POSTN that are relevant to the RUNX1-high POSTN+ fibroblast state.Results
The integrated analyses revealed a significantly expanded RUNX1-high POSTN+ fibroblast subpopulation in HTS and KS. RUNX1 expression was consistently elevated across human skin fibrosis diseases and experimental models of skin fibrosis. Mechanistically, RUNX1 increased the pathogenic properties of POSTN+ fibroblasts by activating ATF4 and POSTN. Through ATF4, RUNX1 increased endoplasmic reticulum stress adaptation and ferroptosis resistance, thereby supporting the ability of POSTN+ fibroblasts to remain activated under stress. Through POSTN, RUNX1 further reinforced fibroblast activation and matrix remodeling. Furthermore, RUNX1 transcriptionally activated MDK, which promoted angiogenesis-associated microenvironmental remodeling through paracrine signaling. Our computational analysis prioritized berberine (BBR) as a candidate compound predicted to bind to POSTN and BBR suppressed RUNX1/POSTN-associated stress-adaptive and profibrotic features in hypertrophic scar fibroblasts. In vivo validation using a bleomycin-induced skin fibrosis mouse model and a mouse scar model supported the antifibrotic potential of targeting RUNX1, and BBR reduced scar formation in a rabbit ear hypertrophic scar model, demonstrating its antiscar therapeutic efficacy.Conclusion
RUNX1 serves as a universal marker and actionable upstream regulator in skin fibrosis diseases. RUNX1-high POSTN+ fibroblasts may contribute to skin fibrosis by increasing the adaptation to ATF4-associated endoplasmic reticulum stress, ferroptosis resistance, persistent fibroblast activation, and vascular microenvironmental remodeling. BBR therefore represents a potential candidate predicted to bind to POSTN for skin fibrosis treatment.
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BibTeX
@article{song2026runx1,
title = {{RUNX1 links ATF4-associated stress adaptation to microenvironmental remodeling in POSTN+ fibroblasts during skin fibrosis.}},
author = {Binyu Song and Yuhan Zhu and Xiang Wang and Yige Han and Junying Song and Kai Wang and Tong Wang and Yixuan Peng and Xiaozi Liu and Zhiwei Cui and Peng Guo and Yajuan Song and Yi Shi and Zhou Yu and Baoqiang Song},
journal = {Burns \& trauma},
year = {2026},
month = sep,
doi = {10.1093/burnst/tkag063},
url = {https://europepmc.org/article/MED/42936794},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - RUNX1 links ATF4-associated stress adaptation to microenvironmental remodeling in POSTN+ fibroblasts during skin fibrosis.
AU - Binyu Song
AU - Yuhan Zhu
AU - Xiang Wang
AU - Yige Han
AU - Junying Song
AU - Kai Wang
AU - Tong Wang
AU - Yixuan Peng
AU - Xiaozi Liu
AU - Zhiwei Cui
AU - Peng Guo
AU - Yajuan Song
AU - Yi Shi
AU - Zhou Yu
AU - Baoqiang Song
PY - 2026
DA - 2026/09/18
JO - Burns & trauma
DO - 10.1093/burnst/tkag063
UR - https://europepmc.org/article/MED/42936794
AB - Background Skin fibrosis encompasses a spectrum of disorders and includes hypertrophic scar (HTS), keloid scar (KS), and systemic sclerosis (SSc), but the pathogenic fibroblast states and shared upstream regulators contributing to these conditions remain incompletely defined. As a common form of skin fibrosis, HTS provides a useful model for elucidating fibroblast heterogeneity and mechanism-based therapeutic vulnerability across skin fibrosis diseases. This study aimed to define the role of RUNX1 in pathogenic POSTN+ fibroblasts during skin fibrosis and to investigate the underlying stress-adaptive and microenvironment-remodeling mechanisms.Methods We performed single-cell RNA sequencing, spatial transcriptomic analysis, multiomics profiling, and cell-cell communication analysis to identify pathogenic fibroblast subpopulations and their regulatory networks in HTS. RUNX1-centered mechanisms were analyzed by CUT&Tag, RNA sequencing, rescue experiments, and functional assays, followed by in vitro and in vivo validation. High-throughput virtual screening and structural analyses were used to computationally prioritize candidate compounds predicted to bind to POSTN that are relevant to the RUNX1-high POSTN+ fibroblast state.Results The integrated analyses revealed a significantly expanded RUNX1-high POSTN+ fibroblast subpopulation in HTS and KS. RUNX1 expression was consistently elevated across human skin fibrosis diseases and experimental models of skin fibrosis. Mechanistically, RUNX1 increased the pathogenic properties of POSTN+ fibroblasts by activating ATF4 and POSTN. Through ATF4, RUNX1 increased endoplasmic reticulum stress adaptation and ferroptosis resistance, thereby supporting the ability of POSTN+ fibroblasts to remain activated under stress. Through POSTN, RUNX1 further reinforced fibroblast activation and matrix remodeling. Furthermore, RUNX1 transcriptionally activated MDK, which promoted angiogenesis-associated microenvironmental remodeling through paracrine signaling. Our computational analysis prioritized berberine (BBR) as a candidate compound predicted to bind to POSTN and BBR suppressed RUNX1/POSTN-associated stress-adaptive and profibrotic features in hypertrophic scar fibroblasts. In vivo validation using a bleomycin-induced skin fibrosis mouse model and a mouse scar model supported the antifibrotic potential of targeting RUNX1, and BBR reduced scar formation in a rabbit ear hypertrophic scar model, demonstrating its antiscar therapeutic efficacy.Conclusion RUNX1 serves as a universal marker and actionable upstream regulator in skin fibrosis diseases. RUNX1-high POSTN+ fibroblasts may contribute to skin fibrosis by increasing the adaptation to ATF4-associated endoplasmic reticulum stress, ferroptosis resistance, persistent fibroblast activation, and vascular microenvironmental remodeling. BBR therefore represents a potential candidate predicted to bind to POSTN for skin fibrosis treatment.
SN - 2321-3868
SN - 2321-3876
ER -