Balancing metabolism and regeneration in liver diseases through HNF4α targeting

Transcription factor hepatocyte nuclear factor 4 alpha (HNF4α) is considered the master regulator of hepatocyte differentiation. During homeostasis, HNF4α maintains liver identity by supporting metabolism while inhibiting proliferation. It is downregulated in response to both acute and chronic insults; however, although this supports hepatic regeneration in mild acute settings, severe or chronic downregulation may further compromise liver function and lead to a lethal outcome. Here, we provide an overview of liver diseases associated with downregulation, altered expression, or dysfunction of HNF4α and suggest the potential underlying mechanisms. We further propose that therapy with Hnf4a mRNA or HNF4α agonists to reactivate HNF4α may be beneficial in pathophysiological contexts characterized by loss of liver function.