期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 903, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174137
关键词
Liver fibrosis; Runt-related transcription factor 1; Ubiquitin-specific protease 9X; SMAD1; HSC activation
资金
- Yunnan Science and Technology Department and Kunming Medical University Special Fund [202001AY070001-229]
In this study, it was found that the expression of RUNX1 was upregulated in LF mice, and RUNX1 knockdown alleviated CCl4-induced LF. RUNX1 silencing reduced the viability and migration of HSCs. Besides, as a transcription factor, RUNX1 bound to the promoter of USP9X and regulated the expression of USP9X. USP9X, a deubiquitination enzyme, was found to be upregulated in LF mice. Silencing of USP9X reduced the viability and migration of HSCs, thereby inhibiting LF.
Liver fibrosis (LF) is a common pathological process with high morbidity and mortality. Runt-related transcription factor 1 (RUNX1) is a transcription factor that could cause nephropathy and renal fibrosis, but its role in LF is unclear. Therefore, this study aimed to investigate the role RUNX1 in LF. Briefly, hepatic fibrosis was detected by Sirius Red staining. Transcript levels were quantified by qPCR, and proteins were assessed by western blotting or immunofluorescence. Cell viability and cell migration were measured by CCK8 assays and wound healing assays, respectively. The binding of RUNX1 and ubiquitin-specific protease 9X (USP9X) promoter was validated by ChIP assays and luciferase report assays, while the binding of USP9X and SMAD1 was confirmed by co-immunoprecipitation (Co-IP). Our studies found that the expression of RUNX1 was upregulated in LF mice, and RUNX1 knockdown alleviated CCl4-induced LF. RUNX1 silencing reduced the viability and migration of HSCs. Besides, RUNX1, as a transcription factor, bound to the promoter of USP9X and regulated the expression of USP9X. USP9X is a deubiquitination enzyme and was found to be up-regulated in LF mice. USP9X silencing reduced the viability and migration of HSCs, thereby inhibiting LF. Further studies showed that USP9X could stabilize downstream Smad1 expression. Furthermore, we also found that RUNX1 regulated the expression of SMAD1 by transcriptionally activating the expression of USP9X, thereby regulating the activation of hepatic stellate cells and liver fibrosis.
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