2. Academic Validation
  3. CircSETD2 impairs hepatic lipid homeostasis in metabolic dysfunction-associated fatty liver disease by binding CPS1

CircSETD2 impairs hepatic lipid homeostasis in metabolic dysfunction-associated fatty liver disease by binding CPS1

  • Int J Biol Macromol. 2025 Dec;333(Pt 2):148879. doi: 10.1016/j.ijbiomac.2025.148879.
Xuancheng Xie 1,  Hongjie Fan 2,  Mengyao Zheng 3,  Ying Zhou 4,  Xingli Liu 1,  Yue Zhai 1,  Wei Song 1,  Lihong Yang 3,  Gang Wang 5,  Dingyun You 6,  Jinhui Yang 7
Affiliations

Affiliations

  • 1 Department of Radiology, the First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China; Department of Radiology, the Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China.
  • 2 Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
  • 3 Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, Yunnan, China.
  • 4 Department of Gastroenterology, the Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China.
  • 5 Department of Radiology, the First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China; Department of Radiology, the Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China. Electronic address: [email protected].
  • 6 School of Public Health, Kunming Medical University, Kunming, 650500, Yunnan, China. Electronic address: [email protected].
  • 7 Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, Yunnan, China. Electronic address: [email protected].
PMID: 41224057 DOI: 10.1016/j.ijbiomac.2025.148879
Abstract

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.

Keywords

Circular RNAs (circRNAs); Lipid metabolism; Metabolic dysfunction-associated fatty liver disease (MAFLD); RNA binding protein.

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