Mechanism of vildagliptin-induced liver injury: An idiosyncratic drug reaction mediated by inflammasome activation

Vildagliptin has been reported to cause liver injury, with clinical findings suggesting the involvement of the immune response. However, the underlying mechanism remains unclear. Vildagliptin possesses a covalent-binding group that may induce an immune response via inflammasome activation. In this study, we examined whether covalent binding of vildagliptin to proteins in differentiated THP-1 or FLC-4 cells leads to inflammasome activation either directly or via damage-associated molecular patterns (DAMPs). We also performed biochemical and histopathological assessments of liver injury in PD-1^-/- mice treated with anti-CTLA-4 antibody and vildagliptin (0.13%). Vildagliptin didn't directly induce IL-1β production and Caspase-1 activity in differentiated THP-1 cells. In contrast, the culture medium of FLC-4 cells incubated with vildagliptin exhibited increased levels. The levels of heat shock protein 40 (HSP40), a DAMP that triggers inflammasome activation, were significantly increased in the culture supernatant. In addition, adducts with a trapping agent were detected in FLC-4 cells, suggesting that covalent binding of vildagliptin induces the release of DAMPs. In mice with impaired immune tolerance due to immune checkpoint blockade, serum AST and ALT levels were significantly elevated 4 weeks after treatment with vildagliptin, and marked granulomatous inflammation was observed in the liver tissues. These results indicate that vildagliptin-induced liver injury occurs via a mechanism whereby the covalent binding of vildagliptin induces the release of HSP40 from hepatocytes, in turn activating inflammasomes. We further demonstrated that the risk of vildagliptin-induced liver injury may be increased by impaired immune tolerance, such as that caused by the co-administration of immune checkpoint inhibitors.