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SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPβ-PAK6 axis in ulcerative colitis

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Abstract

Emerging evidence suggests that ferroptosis is involved in the pathogenesis of ulcerative colitis (UC). However, the key regulator of this process remains uncertain. In this study, we aimed to explore the roles of solute carrier (SLC) family 6 member 14 (SLC6A14) in regulating ferroptosis in UC. The expression of SLC6A14 was significantly increased and positively associated with that of prostaglandin-endoperoxide synthase 2 (PTGS2) in tissue samples from patients with UC. Moreover, a series of in vitro and in vivo experiments showed that SLC6A14 knockdown markedly suppressed ferroptosis. RNA sequencing revealed that SLC6A14 inhibited the expression of P21 (RAC1)-activated kinase 6 (PAK6) and that PAK6 knockdown abolished the effects of SLC6A14 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in Caco-2 cells. Furthermore, chromatin immunoprecipitation (ChIP) and Western blot analysis demonstrated that SLC6A14 negatively regulated PAK6 expression in a CCAAT enhancer binding protein beta (C/EBPβ)-dependent manner. Collectively, these findings indicate that SLC6A14 facilitates ferroptosis in UC by promoting C/EBPβ expression and binding activity to inhibit PAK6 expression, suggesting that targeting SLC6A14-C/EBPβ-PAK6 axis-mediated ferroptosis may be a promising therapeutic alternative for UC.

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Data availability

The microarray datasets analysed during the current study are available in the GEO (GSE134025) repository, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134025.

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Funding

This work was supported by The National Natural Science Foundation of China [Grant numbers 82073156, 81802843]; The Natural Science Foundation of the Jiangsu Higher Education Institutions of China [Grant number 20KJA310005]; Key Project of Medical Research of Jiangsu Commission of Health [Grant number ZDA2020008]; and Graduate Research & Practice Innovation Program of Jiangsu Province [Grant number KYCX21_2970].

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Authors and Affiliations

  1. Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Yanjun Chen, Yuqi Chen, Jinghan Zhu, Jiayu Wang, Haiyan Jin, Hongya Wu, Guangbo Zhang, Shenghua Zhan & Tongguo Shi

  2. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Yanjun Chen, Yuqi Chen, Jinghan Zhu, Jiayu Wang, Qinhua Xi & Weichang Chen

  3. Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China

    Guangbo Zhang, Shenghua Zhan, Tongguo Shi & Weichang Chen

  4. Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu, China

    Guangbo Zhang, Tongguo Shi & Weichang Chen

  5. Center for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China

    Wenying Yan

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Contributions

YJC, TGS, and WCC contributed to the study conception and design. Material preparation, data collection, and analysis were performed by YJC, WYY, JYW, YQC, JHZ, HYJ, HYW, GBZ, TGS, QHX, and SHZ. The first draft of the manuscript was written by YJC and TGS, and all authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Tongguo Shi or Weichang Chen.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

All animal procedures were performed in line with the principles of the Ethics Committee of Soochow University (reference number: SUDA20210918A01). All studies for human tissue samples complied the Ethics Committee of the First Affiliated Hospital of Soochow University (reference number: 2021-325).

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Chen, Y., Yan, W., Chen, Y. et al. SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPβ-PAK6 axis in ulcerative colitis. Cell. Mol. Life Sci. 79, 563 (2022). https://doi.org/10.1007/s00018-022-04594-7

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