Epimedii Folium (EF) is a popular herbal medicine for bone fracture and joint disease. Unfortunately, EF can cause idiosyncratic drug-induced liver injury (IDILI). But the risk factors and mechanisms are not well understood. A new study investigated the liver-damaging effects of the EF compound Icariside I and its effects on the NLRP3 inflammasome a sensor and trigger of inflammatory signals that’s been implicated in IDILI. In cell culture, NLRP3 inflammasome activation by ATP or Nigericin was enhanced by Icariside I. But there was no effect when the inflammasome was activated by SiO2, poly(I:C), or cytosolic lipopolysaccharide. Icariside I alone doesn’t induce mitochondrial reactive oxygen species, a key component of liver damage, but it increases their production after activation by ATP or Nigericin. In an IDILI-susceptible mouse model, the administration of Icariside I induced liver damage, but mice pre-treated with an NLRP3 inhibitor showed no signs of liver damage. Taken together, these results suggest that Icariside I could be causative in idiosyncratic liver injury by promoting NLRP3 inflammasome activation. Future studies should explore ATP- or Nigericin-induced NLRP3 inflammasome activation-related diseases as risk factors for IDILI.