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KLF15-Cyp3a11 Axis Regulates Rifampicin-Induced Liver Injury

Wanqing Hou1, Ku-Geng Huo1, Xiaohua Guo1

  • 1Department of Hepatobiliary Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China (W.H., X.G.); Cyagen Biosciences (Guangzhou) Inc. Guangzhou, Guangdong, China (K.-G.H.); Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, China (M.X., Y.Y., Z.S., J.T., Z.M., S.H.); Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio (W.X.); and Lantu Biopharma, Guangzhou, China (T.G.).

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|April 26, 2024
PubMed

Insights

Krüppel-like factor 15 (KLF15) regulates the detoxification of Rifampicin (RFP). Suppressing KLF15 boosts the RFP-detoxifying enzyme Cyp3a11, reducing liver injury and restoring function in mice.

Area of Science:

  • Pharmacology
  • Hepatology
  • Molecular Biology

Background:

  • Rifampicin (RFP) is crucial for treating tuberculosis but causes significant liver toxicity.
  • Reducing RFP toxicity is vital for its clinical application, with deacetylation showing promise.

Purpose of the Study:

  • To investigate the role of Krüppel-like factor 15 (KLF15) in Rifampicin (RFP) detoxification and associated liver injury.
  • To identify regulatory pathways involved in RFP-induced hepatotoxicity.

Main Methods:

  • Investigated the KLF15-Cyp3a11 interaction in mouse models.
  • Utilized knockout and overexpression models of hepatic KLF15.
  • Assessed liver injury markers and mortality rates following RFP administration.

Main Results:

  • KLF15 was found to repress the expression of the RFP detoxification enzyme Cyp3a11.
  • Knockout of KLF15 increased Cyp3a11 expression, significantly reducing RFP hepatotoxicity in mice.
  • Overexpression of KLF15 worsened RFP-induced liver injury and mortality.

Conclusions:

  • The KLF15-Cyp3a11 axis is a novel regulatory pathway in RFP detoxification.
  • Targeting hepatic KLF15 offers a potential strategy to mitigate Rifampicin-induced liver injury.

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