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Transcriptome-based chemical screens identify several compounds facilitate cellular reprogramming [T_Irak4_XEN_RNAseq]

ABSTRACT: Chemical reprogramming of somatic cells into pluripotent or lineage-specific cells offers transformative potential for regenerative medicine but is limited by molecular barriers. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), a key innate immune kinase, as a previously unrecognized barrier to multi-lineage reprogramming. We discovered that pharmacological inhibition of IRAK4 potently enhances reprogramming of mouse embryonic fibroblasts (MEFs) through the chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, significantly increasing colony formation and expression of core XEN regulators (Sox17/Gata4/Sall4/Foxa2). Genetic knockdown of Irak4 similarly accelerated reprogramming, while its overexpression blocked cell fate transitions. Mechanistically, IRAK4 inhibition remodels cell cycle dynamics, shortening G0/G1 and lengthening G2/M phases to license transcriptional plasticity. Crucially, IRAK4 suppression also enhanced direct lineage conversion, boosting the efficiency and functional maturity of MEF-derived hepatocyte-like cells (iHeps) via elevated albumin/Cyp3a11 expression, glycogen storage, and detoxification capacity. These results establish IRAK4 as a druggable regulator that constrains cellular plasticity by coupling innate immune signaling to cell cycle control. Targeting IRAK4 refines reprogramming strategies to overcome somatic barriers, enhancing the generation of pluripotent and functional lineage-specific cells for regenerative applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE303073 | GEO | 2026/09/02

REPOSITORIES: GEO

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