1. Academic Validation
  2. Doxorubicin promotes NK cell dysfunction and induces acute liver injury through kynurenine-AhR axis

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

  • Int Immunopharmacol. 2025 Mar 19:153:114489. doi: 10.1016/j.intimp.2025.114489.
Bohuai Tang 1 Huan Ouyang 2 Shuping Zheng 3 Le Yu 1 Ruiying Xiao 1 Linqing Wu 4 Zengbin Wang 5
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China.
  • 2 Department of Cardiovascular, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350004, China.
  • 3 Public Technology Service Center, Fujian Medical University, Fuzhou, 350122, China.
  • 4 Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China. Electronic address: wulinqing@fjmu.edu.cn.
  • 5 Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China. Electronic address: wangzengbin@fjmu.edu.cn.
Abstract

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.

Keywords

DILI; Doxorubicin; IDO2; L-kynurenine; NK cell.

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