Icariside Ⅱ, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation

Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely used herbal medicine,has shown to cause idiosyncratic liver injury,but the underlying mechanisms are poorly understood.Increasing evidence has indicated that most cases of IDILI are immune mediated.Here,we report that icarisideⅡ(ICSⅡ),the major active and metabolic constituent of EF,causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation.ICSⅡexacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate(ATP)and nigericin,but not silicon dioxide(SiO2),monosodium urate(MSU)crystal or cytosolic lipopolysaccharide(LPS).Additionally,the activation of NLRC4 and AIM2 inflammasomes is not affected by ICSⅡ.Mechanistically,synergistic induction of mitochondrial reactive oxygen species(mtROS)is a crucial contributor to the enhancing effect of ICSⅡon ATP-or nigericin-induced NLRP3 inflammasome activation.Importantly,in vivo data show that a combination of non-hepatotoxic doses of LPS and ICSⅡcauses the increase of aminotransferase activity,hepatic inflammation and pyroptosis,which is attenuated by Nlrp3 deficiency or pretreatment with MCC950(a specific NLRP3 inflammasome inhibitor).In conclusion,these findings demonstrate that ICSⅡcauses idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICSⅡmay be a risk factor and responsible for EF-induced liver injury.