Role of metabolic nuclear receptors in acute liver injury and drug-induced hepatotoxicity

Metabolic nuclear receptors (NRs) are ligand-activated transcription factors central to metabolic homeostasis and detoxification. While their roles in chronic liver diseases have been reviewed, comprehensive reviews specifically addressing the role of metabolic NRs in acute liver injury (ALI) are limited. This review summarizes how metabolic NRs modulate ALI, focusing on well-characterized NRs including the farnesoid X receptor, peroxisome proliferator-activated receptors and pregnane X receptor, as well as on the less-studied ones such as the liver X receptor and constitutive androstane receptor. Current evidence indicates that activation of farnesoid X receptor, peroxisome proliferator-activated receptor α, and liver X receptor is hepatoprotective against ALI, while activation of proliferator-activated receptor γ, pregnane X receptor, and constitutive androstane receptor potentiate acetaminophen-induced hepatotoxicity and ALI, albeit conclusions from some studies are context-dependent and not definitive. The current review summarizes the roles and mechanisms for how metabolic NRs influence ALI, which would help guide future research on the potential for metabolic NRs in treating ALI.