Targeting the RUNX1 gene helps reduce severe skin fibrosis

Skin fibrosis includes hypertrophic scar (HTS), keloid scar (KS), and systemic sclerosis (SSc). These conditions share persistent fibroblast activation, excessive extracellular matrix (ECM) deposition, and progressive skin remodeling. Single-cell studies have shown that fibroblasts are not one uniform population, but the shared pathogenic states and upstream regulators across skin fibrosis remain unclear.

Periostin-positive (POSTN+) fibroblasts are emerging as an activated state in several organs, yet their role in skin fibrosis and the mechanisms that keep them pathogenic are not well defined. Fibrotic skin also imposes endoplasmic reticulum (ER) stress, oxidative stress, and proteostatic burden.

Because of these challenges, further research is needed to define the upstream regulators and therapeutic vulnerabilities of POSTN+ fibroblasts in skin fibrosis. The study was conducted by researchers at the Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China, and published (DOI: 10.1093/burnst/tkag063) in Burns & Trauma on 18 September 2026.

Using single-cell RNA sequencing, spatial transcriptomics, cleavage under targets and tagmentation (CUT&Tag), RNA sequencing, and animal models, the team studied RUNX family transcription factor 1 (RUNX1) in POSTN+ fibroblasts. They reported that RUNX1 silencing reduced skin fibrosis in mice, while berberine (BBR) reduced scar formation in a rabbit ear model.

The researchers found a RUNX1-high POSTN+ fibroblast population that expanded in HTS and KS, with similar signals in SSc. RUNX1 directly activated ATF4 (activating transcription factor 4), POSTN (periostin), and MDK (midkine). Through ATF4, it strengthened ER stress adaptation by increasing BiP (binding immunoglobulin protein), phosphorylated PERK (protein kinase RNA-like endoplasmic reticulum kinase), and phosphorylated eIF2α (eukaryotic translation initiation factor 2 alpha).

It also raised SLC7A11 (solute carrier family 7 member 11) and GPX4 (glutathione peroxidase 4) protein levels, lowered lipid reactive oxygen species (ROS), Fe2+, and malondialdehyde (MDA), and maintained glutathione (GSH), helping cells avoid ferroptosis. Overexpression of ATF4 partially reversed the effects of RUNX1 loss.

Through MDK, these fibroblasts promoted endothelial migration, proliferation, and tube formation; recombinant MDK restored these functions after RUNX1 silencing. Virtual screening prioritized BBR, which suppressed RUNX1/POSTN-related stress adaptation and profibrotic markers. In mice, AAV9 (adeno-associated virus serotype 9)-mediated RUNX1 silencing reduced dermal thickness, collagen deposition, and POSTN, alpha-smooth muscle actin (α-SMA), ATF4, and GPX4 signals.

In rabbit ear scars, BBR reduced scar thickness, collagen, and α-SMA. The authors said the findings reframe RUNX1 as more than a marker of fibroblast activation. They said it appears to sit upstream of a stress-adaptive program that helps pathogenic POSTN+ fibroblasts survive ER stress and ferroptosis while reshaping the surrounding niche.

They said the RUNX1-ATF4-POSTN/MDK axis may explain why these cells persist and promote vascular changes in scars. They also said BBR's effects support this fibroblast state as a candidate therapeutic vulnerability, while cautioning that cell-specific targeting is still needed. The study points to RUNX1-high POSTN+ fibroblasts as a shared feature of HTS, KS, and SSc, with potential value as a biomarker and drug target.

Because transcription factors are difficult to drug directly, the authors turned to POSTN and identified BBR as a candidate compound predicted to bind it. BBR reduced profibrotic and stress-adaptive features in hypertrophic scar fibroblasts (HTSFs) and reduced scar formation in a rabbit ear model.

AAV9-mediated RUNX1 silencing also attenuated bleomycin-induced skin fibrosis and scar formation in mice. Before clinical translation, however, fibroblast-specific targeting, safety, dosing, and human validation are needed. The work supports further testing of RUNX1/POSTN-directed strategies in skin fibrosis.

Source: Journal reference: Song, B., et al . (2026). RUNX1 links ATF4-associated stress adaptation to microenvironmental remodeling in POSTN+ fibroblasts during skin fibrosis. Burns & Trauma .

DOI: 10.1093/burnst/tkag063. https://academic.oup.com/burnstrauma/advance-article/doi/10.1093/burnst/tkag063/8817336 Suggested Reading Terms While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors.

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