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IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages.
Chuanshu Huang1,2, Xiaoyun Han3, Tao Wang4
1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China. huangchuanshu@ojlab.AC.cn.
EMBO Reports
|July 15, 2026
Summary
Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) inhibits cell reprogramming. Inhibiting IRAK4 promotes regenerative medicine by enhancing cell fate transitions and functional maturity in converted cells.
Area of Science:
- Cell biology
- Regenerative medicine
- Molecular biology
Background:
- Chemical reprogramming offers promise for regenerative medicine.
- Understanding cell fate transition regulation is crucial.
- Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is identified as a key regulator.
Purpose of the Study:
- To investigate the role of IRAK4 in chemical reprogramming.
- To determine if IRAK4 inhibition can enhance cell fate transitions.
- To explore the mechanisms by which IRAK4 affects cellular plasticity.
Main Methods:
- Pharmacological inhibition and genetic knockdown of IRAK4 in mouse embryonic fibroblasts (MEFs).
- Analysis of reprogramming efficiency, colony formation, and gene expression.
- Assessment of chromatin accessibility and cell cycle dynamics.
- Evaluation of functional maturity in directly converted cells.
Main Results:
- IRAK4 inhibition significantly enhanced multi-lineage reprogramming via chemically activated multi-lineage priming (CaMP) and extraembryonic endoderm (XEN)-like states.
- Genetic knockdown of Irak4 accelerated reprogramming, while overexpression blocked it.
- IRAK4 suppression improved chromatin accessibility and altered cell cycle dynamics.
- Direct conversion to neuron-like and hepatocyte-like cells was enhanced, showing improved functional maturity.
Conclusions:
- IRAK4 acts as a barrier to multi-lineage reprogramming and constrains cellular plasticity.
- IRAK4 inhibition is a promising strategy to advance regenerative medicine applications.
- IRAK4's regulation of chromatin accessibility and cell cycle dynamics is key to its role in cell fate determination.
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