Norcantharidin down-regulates iron contents in the liver and spleen of lipopolysaccharide-treated mice

ABSTRACT

Objective

The inhibiting effect of Norcantharidin (NCTD) on IL-6 (interleukin-6) and STAT3 and the involvement of the IL-6/STAT3 pathway in hepcidin expression prompted us to speculate that NCTD could affect iron metabolism.

Methods

We examined the effects of NCTD on serum iron (SI) and transferrin (Tf) saturation, iron and ferritin light chain (FTL), transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1), iron regulatory protein 1 (IRP1) and hepcidin, as well as IL-6 and STAT3 in the liver, spleen and duodenum of mice treated with lipopolysaccharide (LPS) in vivo, using RT-PCR, Western blotting and immunofluorescence analysis.

Results

NCTD could increase SI and Tf saturation and reduce tissue iron and FTL content by affecting expression of cell-iron transport proteins TfR1, DMT1 and Fpn1. The impact of NCTD on TfR1, DMT1 and Fpn1 expression is mediated by up-regulating IRP1 and down-regulating hepcidin expression, while NCTD-induced down-regulation of hepcidin is mediated by the IL-6/STAT3 signalling pathway in LPS-treated mice.

Conclusions

NCTD affects iron metabolism by modifying the expression of IL-6/JAK2/STAT3/hepcidin and IRP1 and suggest that the ability of NCTD to reduce tissue iron contents may be a novel mechanism associated with the anti-cancer effects of NCTD.

KEYWORDS:

• Norcantharidin (NCTD)
• tissue iron
• TfR1 and Fpn1
• IRP1 and hepcidin
• IL-6/JAK2/STAT3 signaling pathway
• mice
• liver
• spleen

Acknowledgements

We would like to thank Christopher Qian from The Chinese University of Hong Kong for assisting with the preparation and English revision of this manuscript. Y.X.B. and Z.M.Q. conceived, organized and supervised the study; J.Z., H.M.M., M.Q.S. and J.J.W. performed the experiments and Y.X.B. contributed to the analysis of data. Y.X.B. and Z.M.Q. prepared and wrote the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

The studies in our laboratories were supported by the National Natural Science Foundation of China [grant numbers 31460006, 31571195], Innovation talent team of Science and Technology Department of Guizhou Province (Guizhou science cooperation platform talents [2020]5007) and Zunyi City Science and Technology Plan Project (Talent platform carrier project) (Zunyi City Branch Platform [2020]7).