Inflammasome Activation and Idiosyncratic Drug-induced Liver Injury: Fusion Study of Basic and Real-world Data

Idiosyncratic drug-induced liver injury (IDILI) is particularly problematic due to its severity and unpredictability. Various pathogenic mechanisms have been proposed for IDILI; however, these mechanisms have yet to be comprehensively elucidated. Although the hapten hypothesis has long been posited as a possible pathogenic mechanism, it is believed that other mechanisms may also elicit a strong immune response. We hypothesized that reactive metabolites generated by drug metabolism cause cellular stress and release damage-associated molecular patterns (DAMPs) that may activate antigen-presenting cells (APCs). We have shown that the metabolites of drugs such as acetaminophen, flutamide, and bicartamide activate the inflammasome response in APCs. Moreover, we confirmed that these reactions are suppressed by steroids. Meanwhile, we are also investigating drugs that are suspected to have an immune-mediated mechanism of action based on basic studies using real-world data. If the pathogenic mechanism of IDILI is indeed immune-mediated, it may be suppressed by steroid administration or activated by the concomitant use of immune checkpoint inhibitors. Additionally, we are analyzing the relative risk rates of these drugs in combination. In this review, we present the findings of our previous studies on the pathogenesis of IDILI, including those on reactive metabolites and immune activation. We also present the results of the real-world data analysis which validated the pathogenic mechanism of IDILI that was previously elucidated through basic research, showcasing our efforts to integrate basic and clinical research.