Integrative transcriptomic and computational analysis associates Ms4a6c+ macrophages with fibrosis in radiation proctitis and computationally nominates MOTS-c as a candidate modulator
- 1Key Laboratory for Precision Digestive Surgery and Intestinal Homeostasis, Department of General Surgery, The Second Affiliated Hospital of Army Medical University
Abstract
Background: Chronic radiation proctitis (CRP) represents a significant clinical challenge characterized by irreversible fibrosis and a lack of specific pharmacological interventions. This study aimed to elucidate the cellular mechanisms underlying impaired tissue repair to identify novel therapeutic targets.
Methods: We employed an integrative framework combining machine learning with bulk and high-resolution single-cell transcriptomic profiling in a murine CRP model. Computational mechanistic analyses included regulon inference, cell-cell communication analysis, and single-cell virtual knockout simulation. The pro-fibrotic association of the identified macrophage subset was further examined using independent single-cell datasets from liver cirrhosis and idiopathic pulmonary fibrosis. Furthermore, structure-based virtual screening and molecular dynamics simulations were conducted to identify potential pharmacological modulators.
Results: We identified Ms4a6c as a key candidate gene exclusively expressed in a distinct, hybrid-activation macrophage subpopulation associated with pro-fibrotic transcriptional programs. These macrophages showed predicted associations with fibrosis via Thbs1-Cd47 paracrine signaling interactions with fibroblasts, and SCENIC regulon analysis identified Cebpb as a candidate upstream transcriptional regulator. Cross-disease analysis in liver cirrhosis and idiopathic pulmonary fibrosis single-cell datasets indicated that Ms4a6c-high macrophage subsets are consistently associated with elevated epithelial-mesenchymal transition and TGF-β signaling activity, supporting a potentially conserved pro-fibrotic role across organ systems. Furthermore, single-cell virtual knockout simulation predicted that the computational depletion of Ms4a6c may reverse pro-fibrotic transcriptomic signatures. Additionally, molecular docking and dynamics simulations identified the mitochondrial-derived peptide MOTS-c as a top-ranking candidate predicted to target Ms4a6c.
Conclusions: This study highlights the potential pathogenic involvement of Ms4a6c+ macrophages and identifies the Cebpb-Ms4a6c-Thbs1-Cd47 axis as a candidate pro-fibrotic signaling cascade that may be conserved across multiple organ fibrosis models. We propose MOTS-c as a potential pharmacological agent for mitigating radiation-induced intestinal fibrosis, pending experimental validation.
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BibTeX
@article{wang2026integrative,
title = {{Integrative transcriptomic and computational analysis associates Ms4a6c+ macrophages with fibrosis in radiation proctitis and computationally nominates MOTS-c as a candidate modulator}},
author = {Peng Wang and Wei Tao and Hong Wen and Kai Liu and Yuanyuan Fu and Yanze Kan and Teming Li and Zhiqiang Zhang and Weidong Xiao},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1907084},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1907084/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrative transcriptomic and computational analysis associates Ms4a6c+ macrophages with fibrosis in radiation proctitis and computationally nominates MOTS-c as a candidate modulator
AU - Peng Wang
AU - Wei Tao
AU - Hong Wen
AU - Kai Liu
AU - Yuanyuan Fu
AU - Yanze Kan
AU - Teming Li
AU - Zhiqiang Zhang
AU - Weidong Xiao
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1907084
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1907084/full
AB - Background: Chronic radiation proctitis (CRP) represents a significant clinical challenge characterized by irreversible fibrosis and a lack of specific pharmacological interventions. This study aimed to elucidate the cellular mechanisms underlying impaired tissue repair to identify novel therapeutic targets. Methods: We employed an integrative framework combining machine learning with bulk and high-resolution single-cell transcriptomic profiling in a murine CRP model. Computational mechanistic analyses included regulon inference, cell-cell communication analysis, and single-cell virtual knockout simulation. The pro-fibrotic association of the identified macrophage subset was further examined using independent single-cell datasets from liver cirrhosis and idiopathic pulmonary fibrosis. Furthermore, structure-based virtual screening and molecular dynamics simulations were conducted to identify potential pharmacological modulators. Results: We identified Ms4a6c as a key candidate gene exclusively expressed in a distinct, hybrid-activation macrophage subpopulation associated with pro-fibrotic transcriptional programs. These macrophages showed predicted associations with fibrosis via Thbs1-Cd47 paracrine signaling interactions with fibroblasts, and SCENIC regulon analysis identified Cebpb as a candidate upstream transcriptional regulator. Cross-disease analysis in liver cirrhosis and idiopathic pulmonary fibrosis single-cell datasets indicated that Ms4a6c-high macrophage subsets are consistently associated with elevated epithelial-mesenchymal transition and TGF-β signaling activity, supporting a potentially conserved pro-fibrotic role across organ systems. Furthermore, single-cell virtual knockout simulation predicted that the computational depletion of Ms4a6c may reverse pro-fibrotic transcriptomic signatures. Additionally, molecular docking and dynamics simulations identified the mitochondrial-derived peptide MOTS-c as a top-ranking candidate predicted to target Ms4a6c. Conclusions: This study highlights the potential pathogenic involvement of Ms4a6c+ macrophages and identifies the Cebpb-Ms4a6c-Thbs1-Cd47 axis as a candidate pro-fibrotic signaling cascade that may be conserved across multiple organ fibrosis models. We propose MOTS-c as a potential pharmacological agent for mitigating radiation-induced intestinal fibrosis, pending experimental validation.
SN - 1664-3224
ER -