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Abstract Liver is an organ with notable capacity of regeneration. Reprogramming of hepatocytes towards an immature state is one of the important mechanisms for hepatocyte replenishment. Inflammatory response mediated by IL-6 and its family cytokines has been widely reported closely related with tissue regeneration in myriads of organs. Recently Hui and colleagues reported that the dedifferentiation of hepatocytes depends upon IL-6 signaling from Kupffer cells and the reprogramming of gene expression under the inflammatory condition is different from the regulation of gene expression during embryo hepatocyte specification, highlighting a tight linkage between extracellular microenvironment and parenchymal cell plasticity during tissue regenerative repair.