Interferon regulatory factor 1: a key transcriptional node orchestrating macrophage polarization: mechanisms and therapeutic potential
- 1Department of Respiratory and Critical Care Medicine, The First Hospital of China Medical University
Abstract
Macrophageexhibit remarkable functional plasticity and adopt M1-like pro-inflammatory or M2-like anti-inflammatory/pro-resolving states in response to microenvironmental stimuli. Notably, this binary functional classification originates largely from in-vitro experimental systems; tissue-resident macrophages in vivo display a continuous spectrum of activation phenotypes rather than discrete subsets. Dysregulated macrophage polarization drives the pathogenesis of infectious diseases, malignancies, and metabolic-inflammatory disorders. Interferon regulatory factor 1 (IRF1) is a pivotal transcription factor governing macrophage fate, yet its multilayered regulatory circuits and context-dependent dual impacts on M1-like and M2-like transcriptional programs remain to be systematically summarized. This review synthesizes recent advances in IRF1-centered regulatory networks of macrophage polarization. We recapitulate IRF1 crosstalk with core signaling cascades including JAK/STAT, TLR/MyD88 and IFN-γ pathways, as well as its transcriptional control of target genes such as iNOS, IL-12, and CXCL10. Multi-layer regulatory mechanisms modulating IRF1 activity are outlined, including transcriptional, epigenetic, non-coding-RNA-mediated post-transcriptional, and post-translational modifications. We further dissect IRF1-linked immunometabolic reprogramming and epigenetic remodeling, and describe its versatile pathophysiological roles in infection, cancer and metabolic inflammatory diseases based on multi-omics and single-cell sequencing evidence. Collectively, this review illustrates IRF1 as a key transcriptional node that orchestrates macrophage polarization, and highlights prospective therapeutic targets and intervention strategies for IRF1-associated immune-mediated disorders.
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BibTeX
@article{cao2026interferon,
title = {{Interferon regulatory factor 1: a key transcriptional node orchestrating macrophage polarization: mechanisms and therapeutic potential}},
author = {Shuqi Cao and Shuang Feng and Yue Gao and Zhiyuan Sun and Shiyao Bai and Xinming Su},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1884705},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1884705/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Interferon regulatory factor 1: a key transcriptional node orchestrating macrophage polarization: mechanisms and therapeutic potential
AU - Shuqi Cao
AU - Shuang Feng
AU - Yue Gao
AU - Zhiyuan Sun
AU - Shiyao Bai
AU - Xinming Su
PY - 2026
DA - 2026/10/21
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1884705
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1884705/full
AB - Macrophageexhibit remarkable functional plasticity and adopt M1-like pro-inflammatory or M2-like anti-inflammatory/pro-resolving states in response to microenvironmental stimuli. Notably, this binary functional classification originates largely from in-vitro experimental systems; tissue-resident macrophages in vivo display a continuous spectrum of activation phenotypes rather than discrete subsets. Dysregulated macrophage polarization drives the pathogenesis of infectious diseases, malignancies, and metabolic-inflammatory disorders. Interferon regulatory factor 1 (IRF1) is a pivotal transcription factor governing macrophage fate, yet its multilayered regulatory circuits and context-dependent dual impacts on M1-like and M2-like transcriptional programs remain to be systematically summarized. This review synthesizes recent advances in IRF1-centered regulatory networks of macrophage polarization. We recapitulate IRF1 crosstalk with core signaling cascades including JAK/STAT, TLR/MyD88 and IFN-γ pathways, as well as its transcriptional control of target genes such as iNOS, IL-12, and CXCL10. Multi-layer regulatory mechanisms modulating IRF1 activity are outlined, including transcriptional, epigenetic, non-coding-RNA-mediated post-transcriptional, and post-translational modifications. We further dissect IRF1-linked immunometabolic reprogramming and epigenetic remodeling, and describe its versatile pathophysiological roles in infection, cancer and metabolic inflammatory diseases based on multi-omics and single-cell sequencing evidence. Collectively, this review illustrates IRF1 as a key transcriptional node that orchestrates macrophage polarization, and highlights prospective therapeutic targets and intervention strategies for IRF1-associated immune-mediated disorders.
SN - 1664-3224
ER -