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

ABSTRACT: Chemical reprogramming of somatic cells into pluripotent or lineage-specific cells offers transformative potential for regenerative medicine but the regulatory mechanism of the cell fate transition is highly elusive. 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 enhances chromatin accessibility and reshapes cell cycle dynamics (G0/G1 shortening and G2/M lengthening), enabling multi-lineage establishment. Moreover, demonstrating the broad role of IRAK4 in restricting cellular plasticity, its suppression also significantly enhanced MEF-to-hepatocyte-like cells (iHeps) direct conversion with ~7-8 folds increasing of Alb⁺Cyp3a11⁺ iHeps, which exhibited enhanced functional maturity including increased glycogen storage and improved detoxification. Collectively, these results demonstrate that IRAK4 constrains cellular plasticity by linking cell plasticity to innate immunity and cell cycle regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE327913 | GEO | 2026/09/02

REPOSITORIES: GEO