CircSETD2 impairs hepatic lipid homeostasis in metabolic dysfunction-associated fatty liver disease by binding CPS1 Article Swipe
Xuancheng Xie
,
Hongjie Fan
,
Mengyao Zheng
,
Ying Zhou
,
Xingli Liu
,
Yue Zhai
,
Wei Song
,
Lihong Yang
,
Gang Wang
,
Dingyun You
,
Jinhui Yang
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1016/j.ijbiomac.2025.148879
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1016/j.ijbiomac.2025.148879
Dysregulation of hepatic lipid homeostasis constitutes a core pathogenic mechanism in metabolic dysfunction-associated fatty liver disease (MAFLD); however, the regulatory role of circular RNAs (circRNAs) in this process remains unclear. In this study, hepatic circRNAs transcriptomic profiling of MAFLD patients identified circSETD2-generated from exons 16-18 of the SETD2 gene-as a stably expressed and significantly upregulated novel circRNA with a closed circular structure localized in the cytoplasm of MAFLD patient liver tissues. Silencing circSETD2 attenuated free fatty acid - induced lipid accumulation in vitro by reducing lipogenesis and enhancing fatty acid β-oxidation. In high fat diet - fed mice, hepatic circSETD2 silencing mitigated steatosis, improved liver function, and reversed dyslipidemia. Mechanistically, RNA pull-down coupled with LC-MS/MS identified carbamoyl phosphate synthetase 1 (CPS1) as a circSETD2-interacting protein, which was subsequently validated by RNA immunoprecipitation and fluorescence in situ hybridization. Pharmacological modulation of CPS1 enzymatic activity in circSETD2-silenced cells established its mediator role. Specifically, circSETD2 directly bound to CPS1, reducing its enzymatic activity and thereby exacerbating lipid metabolic disturbances and disease progression in MAFLD. In summary, circSETD2 drives MAFLD pathogenesis by impairing CPS1-mediated regulation of lipid homeostasis, positioning it as a promising prognostic biomarker and therapeutic target.
Related Topics
Concepts
Lipogenesis
Fatty liver
Lipid metabolism
Gene silencing
Downregulation and upregulation
Fatty acid synthase
Biology
Biochemistry
Endocrinology
Internal medicine
Chemistry
Homeostasis
Fatty acid
Transcriptome
Hepatic stellate cell
Small interfering RNA
Nonalcoholic fatty liver disease
Pathogenesis
Enzyme
Beta oxidation
Mediator
Cell biology
Liver X receptor
RNA
Fatty acid metabolism
MiR-122
Lipid droplet
Eicosapentaenoic acid
Oxidative phosphorylation
Mitochondrion
Fatty acid synthesis
Circular RNA
Metabolic pathway
Steatosis
Cytoplasm
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1016/j.ijbiomac.2025.148879
- OA Status
- hybrid
- References
- 46
- OpenAlex ID
- https://openalex.org/W7104729564
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W7104729564Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1016/j.ijbiomac.2025.148879Digital Object Identifier
- Title
-
CircSETD2 impairs hepatic lipid homeostasis in metabolic dysfunction-associated fatty liver disease by binding CPS1Work title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-11-11Full publication date if available
- Authors
-
Xuancheng Xie, Hongjie Fan, Mengyao Zheng, Ying Zhou, Xingli Liu, Yue Zhai, Wei Song, Lihong Yang, Gang Wang, Dingyun You, Jinhui YangList of authors in order
- Landing page
-
https://doi.org/10.1016/j.ijbiomac.2025.148879Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
hybridOpen access status per OpenAlex
- OA URL
-
https://doi.org/10.1016/j.ijbiomac.2025.148879Direct OA link when available
- Concepts
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Lipogenesis, Fatty liver, Lipid metabolism, Gene silencing, Downregulation and upregulation, Fatty acid synthase, Biology, Biochemistry, Endocrinology, Internal medicine, Chemistry, Homeostasis, Fatty acid, Transcriptome, Hepatic stellate cell, Small interfering RNA, Nonalcoholic fatty liver disease, Pathogenesis, Enzyme, Beta oxidation, Mediator, Cell biology, Liver X receptor, RNA, Fatty acid metabolism, MiR-122, Lipid droplet, Eicosapentaenoic acid, Oxidative phosphorylation, Mitochondrion, Fatty acid synthesis, Circular RNA, Metabolic pathway, Steatosis, CytoplasmTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- References (count)
-
46Number of works referenced by this work
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