Doxorubicin promotes NK cell dysfunction and induces acute liver injury through kynurenine-AhR axis

Drug-induced liver injury (DILI) is one of the significant drug-induced diseases and a major cause of clinically unexplained liver injury and unexplained liver diseases. However, the mechanisms underlying doxorubicin (DOX)-induced DILI remain unclear. In this study, we constructed a mouse model of DOX-induced acute liver injury (ALI) and employed a combination of proteomics, metabolomics, and flow cytometry (FCM) to examine the roles of metabolic processes and innate immune responses. Our findings revealed that DOX treatment altered the metabolic profile and innate immune response signals in mouse livers. Specifically, DOX activated the indoleamine 2,3-dioxygenase 2 (IDO2)-mediated L-Tryptophan/L-Kynurenine metabolic pathway. Further in-depth analysis demonstrated that DOX promoted natural killer (NK) cell dysfunction leading to ALI by activating the kynurenine-aryl hydrocarbon receptor (Kyn-AhR) axis. Importantly, targeting the Kyn-AhR axis could reverse DOX-induced ALI. In summary, this study suggests that targeting the Kyn-AhR axis holds promise as an effective strategy to reverse ALI.