2. Academic Validation
  3. Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis

Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis

  • J Exp Clin Cancer Res. 2024 May 3;43(1):133. doi: 10.1186/s13046-024-03047-2.
Yanmei Yuan 1,  Junting Xu 1,  Quanxin Jiang 1,  Chuanxin Yang 1,  Ning Wang 1,  Xiaolong Liu 2,  Hai-Long Piao 2,  Sijia Lu 1,  Xianjing Zhang 1,  Liu Han 1,  Zhiyan Liu 3,  Jiabin Cai 4,  Fang Liu 5,  Suzhen Chen 6,  Junli Liu 7
Affiliations

Affiliations

  • 1 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
  • 2 Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
  • 3 Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
  • 4 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Shanghai, 200032, China. cai.jiabin@zs-hospital.sh.cn.
  • 5 Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. f-liu@sjtu.edu.cn.
  • 6 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. cszdream@163.com.
  • 7 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. liujunli@sjtu.edu.cn.
PMID: 38698462 DOI: 10.1186/s13046-024-03047-2
Abstract

Background: Targeting Ferroptosis has been identified as a promising approach for the development of Cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting Ferroptosis. Ficolin 3 (FCN3) is a component of the Complement System, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and Ferroptosis remains largely unknown.

Methods: Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect Ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels.

Results: Our study elucidates a substantial decrease in the expression of FCN3, a component of the Complement System, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes Ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to Ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the Insulin Receptor β (IR-β) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-β phosphorylation, ultimately resulting in IR-β inactivation. This inactivation of IR-β suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels.

Conclusions: These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to Ferroptosis, indicating that targeting FCN3-induced Ferroptosis is a promising strategy for HCC treatment.

Keywords

De novo lipogenesis; Ferroptosis; Ficolin 3; Insulin receptor; MUFA.

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