Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.

Automated summary

Recent studies have shown that cirrhosis ranks as the 11th leading cause of death worldwide, highlighting the urgent need for new therapies to slow the progression of liver damage in the early stages. Cholestasis, caused by accumulation of hydrophobic bile acids in the liver, has led to investigations on detoxification strategies and downregulation of genes involved in bile acid production. Dysregulation of FXR signaling has been linked to changes in autophagy due to reactive oxygen species induced by bile acids and increased antioxidant response through NRF2, opening up new avenues for developing more effective therapies.