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6-gingerol alleviates chemotherapy-induced nausea and vomiting by inhibiting ferroptosis via the regulation of iron homeostasis

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Abstract

Purpose

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Chemotherapy-induced nausea and vomiting (CINV) is a common gastrointestinal side effect in cancer treatment. 6-gingerol, a bioactive component of ginger, demonstrates efficacy in attenuating CINV. This study aimed to explore the effects of 6-gingerol on inhibiting ferroptosis and to clarify its potential antiemetic mechanisms in a cisplatin-induced rat pica model.

Methods

We established the rat pica model by intraperitoneal injection of cisplatin (6 mg/kg). The histopathological damage in gastrointestinal (GI) tissues was assessed by hematoxylin-eosin staining. The levels of serum IL-6, IL-1β, TNF-α, and hepcidin were measured by ELISA. The occurrence of ferroptosis was confirmed by measuring the levels of ROS, GSH, SOD, MDA, and iron in GI tissues. Furthermore, iron deposition was visualized with Perls + DAB staining, and the lipid peroxidation product 4-HNE was detected via immunohistochemistry. The expression levels of iron homeostasis-related proteins in GI tissues were examined by western blotting.

Results

The results showed that 6-gingerol improved pica behavior and mitigated GI inflammation in cisplatin-treated rats. Additionally, 6-gingerol mitigated oxidative stress, lipid peroxidation, and reduced iron accumulation. Molecular docking analysis showed that iron homeostasis-related proteins (TfR1, DMT1, ferritin, Fpn, and hepcidin) might be the potential regulatory targets of 6-gingerol. Mechanistically, 6-gingerol restored iron homeostasis by downregulating the expression levels of TfR1 and DMT1 to reduce iron uptake and transport, and upregulating the expression levels of ferritin and Fpn to enhance iron storage and export.

Conclusion

Overall, this study indicates that regulating iron homeostasis to inhibit ferroptosis is related to the therapeutic effect of 6-gingerol against CINV.

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Data availability

Data will be made available on request.

Abbreviations

4-HNE:

4-hydroxynonenal

5-HT:

5-hydroxytryptamine

5-HT3R:

5-hydroxytryptamine 3 receptor

CINV:

Chemotherapy-induced nausea and vomiting

DAMPs:

Damage-associated molecular patterns

DMT1:

Divalent metal transporter 1

Fpn:

Ferroportin

FTH1:

Ferritin heavy chain 1

FTL:

Ferritin light chain

GI:

Gastrointestinal

GSH:

Glutathione

HE:

Hematoxylin-eosin staining

IHC:

Immunohistochemistry

IL-1β:

Interleukin-1 beta

IL-6:

Interleukin-6

MDA:

Malondialdehyde

NK-1R:

Neurokinin 1 receptor

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

SP:

Substance P

TfR1:

Transferrin receptor 1

TNF-α:

Tumor necrosis factor alpha

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Funding

This study was supported by National Natural Science Foundation of China [grant numbers 82174143] and the Innovative Team Project of Ordinary Universities in Guangdong Province [grant numbers 2022KCXTD016].

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Author notes

  1. Wan Liang, Lei Feng and Siyu Han contributed equally to this work and share first authorship.

Authors and Affiliations

  1. School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, P.R. China

    Wan Liang, Lei Feng, Siyu Han, Chenglu Yang, Binbin Ye, Ziyao Mo & Ke Nie

Authors
  1. Wan Liang
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  2. Lei Feng
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  3. Siyu Han
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  4. Chenglu Yang
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  5. Binbin Ye
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  6. Ziyao Mo
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  7. Ke Nie
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Contributions

Wan Liang, Lei Feng, and Siyu Han: conceptualization, investigation, methodology, visualization, and writing-original draft. Chenglu Yang, Binbin Ye, Ziyao Mo: investigation and validation. Ke Nie: conceptualization, funding acquisition, supervision, and writing-review and editing.

Corresponding author

Correspondence to Ke Nie.

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The authors declare no competing interests.

Ethical approval

The whole study was compliant with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines (https://arriveguidelines.org). The animal experiments were approved by the Laboratory Animal Care and Use Committee of Guangdong Pharmaceutical University (ethical license No. gdpulacspf2022084), in accordance with the National Institutes of Health guide for the care and use of Laboratory animals.

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Liang, W., Feng, L., Han, S. et al. 6-gingerol alleviates chemotherapy-induced nausea and vomiting by inhibiting ferroptosis via the regulation of iron homeostasis. Cancer Chemother Pharmacol 95, 119 (2025). https://doi.org/10.1007/s00280-025-04850-0

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