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Int J Biol Sci 2024; 20(7):2422-2439. doi:10.7150/ijbs.92749 This issue Cite

Research Paper

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells

Yawen Hao1,2, Shaohua Song3, Tao Li3, Qiuhong Zai1,2, Ningning Ma1,2, Yixin Li4, Liu Yang1,2, Peng Xiao5, Tianyue Xu1, Longshan Ji6, Jiaxin Tan6, Yeni Ait Ahmed7, Xiaogang Xiang3, Xiaolin Wang3, Fouad Lafdil8,9, Qing Xie3✉, Yong He1,2✉

1. Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
2. University of Chinese Academy of Sciences, Beijing, China.
3. Department of General Surgery or Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4. Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China.
5. Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, Jilin, China.
6. Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
7. Medizinische Klinik m. S. Hepatologie und Gastroenterologie Charité Universitätsmedizin Berlin, Germany.
8. Université Paris-Est-Créteil (UPEC), F-94000, Créteil, France.
9. Institut Universitaire de France (IUF), Paris, F-75231 Cedex 05 France.

✉ Corresponding authors: Yong He, Ph.D., Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China; Email: heyongac.cn; Qing Xie, MD., PhD., Department of Infectious Diseases, More

Citation:
Hao Y, Song S, Li T, Zai Q, Ma N, Li Y, Yang L, Xiao P, Xu T, Ji L, Tan J, Ahmed YA, Xiang X, Wang X, Lafdil F, Xie Q, He Y. Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells. Int J Biol Sci 2024; 20(7):2422-2439. doi:10.7150/ijbs.92749. https://www.ijbs.com/v20p2422.htm
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Abstract

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Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown.

Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models.

Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis.

Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

Keywords: AAV6, ROS, HSC, p38, liver fibrogenesis

Citation styles

APA
Hao, Y., Song, S., Li, T., Zai, Q., Ma, N., Li, Y., Yang, L., Xiao, P., Xu, T., Ji, L., Tan, J., Ahmed, Y.A., Xiang, X., Wang, X., Lafdil, F., Xie, Q., He, Y. (2024). Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells. International Journal of Biological Sciences, 20(7), 2422-2439. https://doi.org/10.7150/ijbs.92749.

ACS
Hao, Y.; Song, S.; Li, T.; Zai, Q.; Ma, N.; Li, Y.; Yang, L.; Xiao, P.; Xu, T.; Ji, L.; Tan, J.; Ahmed, Y.A.; Xiang, X.; Wang, X.; Lafdil, F.; Xie, Q.; He, Y. Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells. Int. J. Biol. Sci. 2024, 20 (7), 2422-2439. DOI: 10.7150/ijbs.92749.

NLM
Hao Y, Song S, Li T, Zai Q, Ma N, Li Y, Yang L, Xiao P, Xu T, Ji L, Tan J, Ahmed YA, Xiang X, Wang X, Lafdil F, Xie Q, He Y. Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells. Int J Biol Sci 2024; 20(7):2422-2439. doi:10.7150/ijbs.92749. https://www.ijbs.com/v20p2422.htm

CSE
Hao Y, Song S, Li T, Zai Q, Ma N, Li Y, Yang L, Xiao P, Xu T, Ji L, Tan J, Ahmed YA, Xiang X, Wang X, Lafdil F, Xie Q, He Y. 2024. Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells. Int J Biol Sci. 20(7):2422-2439.

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