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

Abstract

Idiosyncratic drug-induced liver injury (IDILI) is an infrequent 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 icariside Ⅱ (ICS Ⅱ), the major active and metabolic constituent of EF, causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation. ICS Ⅱ exacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) and nigericin, but not silicon dioxide (SiO 2 ), monosodium urate (MSU) crystal or cytosolic lipopolysaccharide (LPS). Additionally, the activation of NLRC4 and AIM2 inflammasomes is not affected by ICS Ⅱ. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial contributor to the enhancing effect of ICS Ⅱ on ATP- or nigericin-induced NLRP3 inflammasome activation. Importantly, in vivo data show that a combination of non-hepatotoxic doses of LPS and ICS Ⅱ causes 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 ICS Ⅱ causes idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICS Ⅱ may be a risk factor and responsible for EF-induced liver injury.

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

“…Both Epimedii Folium and Psoraleae Fructus could induce liver injury according to clinical research (Wang et al, 2016;Melchart et al, 2017). Combination of nonhepatotoxic doses of LPS and icariside II (the major active and metabolic constituent of Epimedii Folium) causes the increase of aminotransferase activity, hepatic inflammation, and pyroptosis, which is attenuated by Nlrp3 deficiency or pretreatment with MCC950 (a specific NLRP3 inhibitor) in vivo and in vitro (Wang et al, 2020). In another study (Wang et al, 2021), eight bioactive compounds involved in Psoraleae Fructus-induced NLRP3 inflammasome activation, among which only psoralidin activated the NLRP3 inflammasomes, followed by secreting caspase-1 and IL-1β in a dose-dependent manner in normal mice.…”

NLRP3 Inflammasome Pharmacological Inhibitors in Glycyrrhiza for NLRP3-Driven Diseases Treatment: Extinguishing the Fire of Inflammation

“…Our previous studies also show that the drugs carbamazepine, isoniazid and nevirapine, as well as Chinese medicines such as Epimedium folium and Psoraleae frucitus, can promote the activation of NLRP3 inflammasome and lead to liver injury. [114][115][116] Therefore, we believe that one of the scientific connotations of the description of Glycyrrhiza's ability to "harmonize all kinds of drugs and cure all kinds of toxins" is the broad spectrum of antagonistic effects: abnormal activation of NLRP3 inflammasome signaling pathway is involved in the occurrence and development of various diseases, and active ingredients in Glycyrrhiza slow the process and reduce the development of related diseases by inhibiting NLRP3 inflammasome, and thus are capable of "mediating various drugs and eliminating all toxins".…”

MicroRNA-1224-5p Aggravates Sepsis-Related Acute Lung Injury in Mice

“…LPS injection directly activates TLR4 and subsequently promoted the phosphorylation and nuclear accumulation of NF-κB, which then drives the transcription of various inflammatory cytokines. The NLRP3 inflammasome functions as a molecular scaffold for the maturation and release of IL-1β and IL-18 [55][56][57]. LPS-triggered ROS generation promotes the dissociation of TXNIP from thioredoxin, which then interacts with NLRP3 to activate NLRP3 inflammasome.…”