Abstract
Downregulation of circ_0044226 has been demonstrated to reduce pulmonary fibrosis, but the role of circ_0044226 in liver fibrosis remains to be explored. In this work, we found that circ_0044226 expression was upregulated during liver fibrosis. Knockdown of circ_0044226 inhibited proliferation, promoted autophagy and apoptosis of hepatic stellate cell LX-2. Bioinformatic analysis and dual luciferase reporter assays confirmed the interaction between circ_0044226, miR-4677-3p and SEC61G. Mechanistically, knockdown of circ_0044226 suppressed SEC61G expression by releasing miR-4677-3p, thereby enhancing endoplasmic reticulum stress. Overexpression of SEC61G or endoplasmic reticulum stress inhibitor 4-phenylbutiric acid partially reversed the effect of knockdown circ_0044226 on LX-2 cell function. In vivo experiments showed that inhibition of circ_0044226 attenuated CCL4-induced liver fibrosis in mice. These imply that circ_0044226 may be a potential target for the treatment of liver fibrosis.
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Shanshan Yuan and Jiaming Liu: Conceptualization and Writing – original draft; Li Yang and Xin Zhang: Formal analysis, Methodology and Writing – review & editing; Kun Zhuang: Data curation and Software; Shuixiang He: Conceptualization, Project administration and Writing – review & editing.
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This study was approved by the ethics committee of The First Affiliated Hospital of Xi'an Jiaotong University. And all animal experiments complied with ARRIVE guidelines, and were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals.
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Shanshan Yuan and Jiaming Liu contribute equally to this study and regarded as co-first author.
Highlights
1. Knockdown of circ_0044226 inhibits the proliferation of activated hepatic stellate cells.
2. Knockdown of circ_0044226 promotes autophagy and apoptosis in activated hepatic stellate cells.
3. Circ_0044226 regulates SEC61G-mediated ERs by sponging miR-4677-3p.
4. Inhibition of circ_0044226 attenuates CCL4-induced liver fibrosis in mice.
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Yuan, S., Liu, J., Yang, L. et al. Knockdown of circ_0044226 promotes endoplasmic reticulum stress-mediated autophagy and apoptosis in hepatic stellate cells via miR-4677-3p/SEC61G axis. J Bioenerg Biomembr (2024). https://doi.org/10.1007/s10863-024-10007-0
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DOI: https://doi.org/10.1007/s10863-024-10007-0