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FTO overexpression expedites wound healing and alleviates depression in burn rats through facilitating keratinocyte migration and angiogenesis via mediating TFPI-2 demethylation

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Abstract

Burn injury is a serious traumatic injury that leads to severe physical and psychosocial impairment. Wound healing after burn injury is a substantial challenge in medical community. This study investigated the biological effects of the demethylase fat mass and obesity-associated protein (FTO) on burn injury. FTO protein level in burn skin tissues of patients was measured with Western blot assay. Keratinocytes (HaCaT cells) were given heat stimulation to induce an in vitro burn injury model, and then transfected with overexpression plasmids of FTO (pcDNA-FTO) or small interfering RNA against FTO (si-FTO). Cell proliferation, migration, and angiogenesis in keratinocytes were evaluated with CCK-8, Transwell, and tube formation assays, respectively. Tissue factor pathway inhibitor-2 (TFPI-2) m6A methylation level was detected with MeRIP‑qPCR assay. Then rescue experiments were conducted to explore the effects of FTO/TFPI-2 axis on keratinocyte functions. Lentivirus carrying FTO overexpression plasmids was injected into a burn rat model to detect its effects on wound healing and depressive-like behaviors in burn rats. FTO was downregulated in burn skin and heat-stimulated keratinocytes. FTO prominently augmented proliferation, migration and angiogenesis in heat-stimulated keratinocytes, while FTO knockdown showed the opposite results. FTO inhibited TFPI-2 expression by FTO-mediated m6A methylation modification. TFPI-2 overexpression abrogated FTO mediated enhancement of proliferation, migration and angiogenesis in keratinocytes. Additionally, FTO overexpression accelerated wound healing and improved depressive-like behaviors in burn rat model. FTO prominently augmented proliferation, migration and angiogenesis in heat-stimulated keratinocytes though inhibiting TFPI-2, and then improved wound healing and depressive-like behaviors.

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Data availability

The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files.

Abbreviations

FTO:

Fat mass and obesity-associated protein

TFPI-2:

Tissue factor pathway inhibitor-2

m6A:

N6‑methyladenosine

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We acknowledge the supports of fundings: Xi'an Science and Technology Plan Project, 2019115013YX005SF038 (6) and the Natural Science Basic Research Program of Shaanxi, 2022JQ-975.

Funding

This research is supported by Xi'an Science and Technology Plan Project, 2019115013YX005SF038 (6) and the Natural Science Basic Research Program of Shaanxi, 2022JQ-975.

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Authors and Affiliations

  1. Department of Burns and Plastic Surgery, Shaanxi Provincial People’s Hospital, Xi’an, 710068, China

    Zihan Xu, Xiumei Zhu, Shengzhi Mu, Ronghui Fan, Benfeng Wang & Wenjie Gao

  2. Department of Neurology, Shaanxi Provincial People’s Hospital, Xi’an, 710068, China

    Tao Kang

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  1. Zihan Xu
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  2. Xiumei Zhu
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Contributions

Xu ZH: Methodology, Investigation, Data curation, Original draft. Zhu XM: Methodology, Investigation, Data curation, Original draft. Mu SZ: Review & editing. Fan RH: Writing, Review & editing. Wang BF: Investigation. Gao WJ: Writing. Kang T: Idea, Supervision, Review & editing.

Corresponding author

Correspondence to Tao Kang.

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The authors declare no competing interests.

Ethical approval

This study has approved by the Ethics Committees of the Shaanxi Provincial People’s Hospital and abided by the ethical guidelines of the Declaration of Helsinki.

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Informed consent was obtained from all individual participants included in the study.

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Xu, Z., Zhu, X., Mu, S. et al. FTO overexpression expedites wound healing and alleviates depression in burn rats through facilitating keratinocyte migration and angiogenesis via mediating TFPI-2 demethylation. Mol Cell Biochem 479, 325–335 (2024). https://doi.org/10.1007/s11010-023-04719-x

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