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Molecular targets for antifibrotic therapy in liver disease: using magic bullets for crossfire rather than a one-sided shotgun attack
  1. Claus Hellerbrand
  1. Correspondence to Professor Claus Hellerbrand, Department of Internal Medicine I, University Hospital Regensburg, Regensburg D-93053, Germany; claus.hellerbrand{at}

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The c-Jun-N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family. Upon activation, JNK regulates various cellular responses, such as differentiation, proliferation, migration, the immune reaction and cell death.1 JNK activation is also involved in multiple pathways in liver physiology and disease pathogenesis.2

There are three isoforms of JNK in mammals. Whereas JNK3 is mainly expressed in the brain, heart and testis, JNK1 and JNK2 are expressed in most cells, including hepatic parenchymal and non-parenchymal cells. JNK1 and JNK2 have typically been considered to have overlapping or redundant functions. However, it is becoming more and more evident that the JNK isoforms exhibit diverse effects in various cell types, depending on the magnitude and duration of activation.1

Hepatic fibrosis is a complex and tightly regulated process that involves various cell types and pathomechanisms. It can be considered as a dysregulated wound healing response to chronic hepatic injury. Activated hepatic stellate cells (HSCs) are the primary effector cells responsible for the extensive extracellular matrix accumulation and scar formation. However, the situation is more complex, as several additional cell types, including parenchymal, non-parenchymal, immune infiltrating and bone marrow cells, play an important role in both the pathogenesis and resolution of liver fibrosis.3 Furthermore, hepatocellular proliferation and apoptosis are critical for tissue regeneration and repair, but when dysregulated, these processes contribute to the malignant transformation of hepatocytes and the development of hepatocellular carcinoma (HCC).3 ,4

Therefore, it is critical to understand the function of distinct JNK isoforms during the various phases and in the various cell types involved in hepatic fibrosis. Examining jnk1 and jnk2 …

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  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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