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IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages.

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Τίτλος: IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages.
Συγγραφείς: Huang C; Zhejiang 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.; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325035, China. huangchuanshu@ojlab.AC.cn., Han X; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325035, China., Wang T; Key Laboratory of Laboratory Medicine, Ministry of Education, Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China., Zhao Y; State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100871, China. yangzhao@pku.edu.cn., Li J; Zhejiang 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. jun.li@wmu.edu.cn.; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325035, China. jun.li@wmu.edu.cn.
Πηγή: EMBO reports [EMBO Rep] 2026 Aug; Vol. 27 (16), pp. 4903-4934. Date of Electronic Publication: 2026 Jul 15.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 100963049 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-3178 (Electronic) Linking ISSN: 1469221X NLM ISO Abbreviation: EMBO Rep Subsets: MEDLINE
Imprint Name(s): Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Oxford, UK : Published for EMBO by Oxford University Press, 2000-
Ιατρικοί όροι (MeSH): Cellular Reprogramming*/drug effects , Cellular Reprogramming*/genetics , Interleukin-1 Receptor-Associated Kinases*/metabolism , Interleukin-1 Receptor-Associated Kinases*/genetics , Interleukin-1 Receptor-Associated Kinases*/antagonists & inhibitors , Cell Lineage*/drug effects , Cell Plasticity*/genetics , Cell Plasticity*/drug effects, Fibroblasts/cytology ; Fibroblasts/metabolism ; Fibroblasts/drug effects ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Endoderm/cytology ; Endoderm/metabolism ; Neurons/cytology ; Neurons/metabolism ; Animals ; Mice ; Cell Cycle ; Cell Differentiation
Περίληψη: Chemical reprogramming holds transformative potential for regenerative medicine. However, the regulatory mechanisms governing cell fate transitions are not well understood. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a barrier to multi-lineage reprogramming. Pharmacological inhibition of IRAK4 enhances the reprogramming of mouse embryonic fibroblasts (MEFs) through a chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, increasing colony formation, and the expression of core XEN regulators (Sox17, Gata4, Sall4, and Foxa2). Genetic knockdown of Irak4 similarly accelerates reprogramming, whereas its overexpression blocks cell fate transitions. IRAK4 inhibition enhances chromatin accessibility and reshapes cell cycle dynamics, characterized by G0/G1 shortening and G2/M lengthening, potentially contributing to multi-lineage state establishment. Furthermore, IRAK4 suppression enhances the direct conversion of MEFs to neuron-like and hepatocyte-like cells, which exhibit enhanced functional maturity, including increased glycogen storage and improved detoxification capacity. Our findings establish IRAK4 as a regulator that constrains cellular plasticity potentially by coordinating chromatin accessibility and cell cycle dynamics.
(© 2026. The Author(s).)
Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests.
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Grant Information: 32400603 MOST | National Natural Science Foundation of China (NSFC); LQ24H110004 MOST | NSFC | NSFC-Zhejiang Joint Fund | | Natural Science Foundation of Zhejiang Province (ZJNSF); KYYW202319 and KYYW202401 Fundamental Research Foundation of wenzhou medical university
Substance Nomenclature: EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases)
Entry Date(s): Date Created: 20260715 Date Completed: 20260825 Latest Revision: 20260903
Update Code: 20260903
PubMed Central ID: PMC13503836
DOI: 10.1038/s44319-026-00855-9
PMID: 42458070
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1469-3178
DOI:10.1038/s44319-026-00855-9