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The following is a summary of “CircDCBLD2 alleviates liver fibrosis by regulating ferroptosis via facilitating STUB1-mediated PARK7 ubiquitination degradation,” published in the February 2024 issue of Gastroenterology by Wang, et al.
If left untreated, liver fibrosis can progress to cirrhosis and hepatic carcinoma. CircDCBLD2, a circular RNA, is downregulated in liver fibrosis. However, the precise mechanism underlying the downregulation required further elucidation.
The study employed various assays, including qRT-PCR, Western blot, immunohistochemistry, and histological staining, to investigate molecular changes and pathological alterations in liver tissues. Flow cytometry and commercial kits were used to assess lipid reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and iron levels. Cell viability was evaluated using MTT assays. Immunoprecipitation was performed to study the ubiquitination of PARK7. Mitophagy was determined by immunostaining and confocal imaging. RNA immunoprecipitation (RIP) and co-immunoprecipitation (Co-IP) assays were conducted to assess the interactions of circDCBLD2/HuR, HuR/STUB1, and STUB1/PARK7. Fluorescence in situ hybridization and immunofluorescence staining were used to evaluate the co-localization of circDCBLD2 and HuR.
They observed that circDCBLD2 was downregulated, while PARK7 was upregulated in liver fibrosis. Activation of ferroptosis increased circDCBLD2 expression while decreasing PARK7 levels in hepatic stellate cells (HSCs). Overexpression of circDCBLD2 reduced cell viability and GSH, PARK7, and GPX4 expression in erastin-treated HSCs while increasing MDA and iron levels. Conversely, circDCBLD2 knockdown had the opposite effects. We found that circDCBLD2 overexpression promoted STUB1-mediated PARK7 ubiquitination degradation by enhancing the binding of HuR to STUB1 mRNA, thereby increasing STUB1 mRNA stability. Furthermore, PARK7 overexpression or HuR knockdown reversed the effects of circDCBLD2 overexpression on HSC activation and ferroptosis. In mice, circDCBLD2 reduced liver fibrosis by inhibiting PARK7.
The findings suggested that circDCBLD2 overexpression enhances liver fibrosis by promoting STUB1-mediated PARK7 ubiquitination degradation, inhibiting HSC activation, and promoting HSC ferroptosis. The study provided insights into the regulatory mechanisms underlying liver fibrosis and suggested potential therapeutic targets for its treatment.
Reference: link.springer.com/article/10.1007/s00535-023-02068-6
