Related Experiment Video

Updated: May 7, 2025

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
08:38

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

Published on: November 8, 2015

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CXCR2 Activated JAK3/STAT3 Signaling Pathway Exacerbating Hepatotoxicity Associated with Tacrolimus

Xiao Chen1, Ke Hu2, Yue Zhang2

  • 1School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China.

Drug Design, Development and Therapy
|January 3, 2025
PubMed
Abstract

Insights

Tacrolimus-induced liver injury is mediated by the CXCR2 pathway. Blocking CXCR2 alleviates liver damage by regulating the JAK3/STAT3 signaling pathway, offering a potential therapeutic target for preventing tacrolimus hepatotoxicity.

Area of Science:

  • Hepatology
  • Immunology
  • Pharmacology

Background:

  • Tacrolimus is a vital immunosuppressant, but its clinical use is limited by potential hepatotoxicity.
  • The precise mechanisms underlying tacrolimus-induced liver injury remain incompletely understood, hindering effective prevention and treatment strategies.

Purpose of the Study:

  • To elucidate the molecular mechanisms of tacrolimus-induced hepatotoxicity.
  • To identify potential therapeutic targets for mitigating tacrolimus-induced liver damage and inform drug development.

Main Methods:

  • Utilized gene knockout mice and Wistar rats for mechanistic studies.
  • Employed biochemical analysis, histopathology, immunofluorescence, immunohistochemistry, transcriptomics, and Western blotting.

Main Results:

  • CXCR2-deficient mice exhibited reduced tacrolimus-induced hepatotoxicity compared to wild-type controls.
  • In Wistar rats, tacrolimus upregulated the CXCL2-CXCR2 axis and JAK3/STAT3 signaling, decreasing CIS and increasing PIM1 expression, leading to liver damage.
  • Inhibition of CXCR2 reversed these molecular changes and ameliorated liver injury.

Conclusions:

  • The CXCR2-activated JAK3/STAT3 signaling pathway exacerbates tacrolimus-induced hepatotoxicity.
  • Downregulation of CIS and upregulation of PIM1 are key events in this pathway.
  • Targeting CXCR2 presents a promising strategy for preventing and treating tacrolimus-induced liver injury.
Keywords:
CISCXCR2JAK3/STAT3 signaling pathwayPIM1hepatotoxicitytacrolimus

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