Fgl1, or Fibrinogen-like protein 1, is a protein secreted mainly by the liver. It plays crucial roles in multiple biological processes. Fgl1 is a key ligand of lymphocyte activation gene 3 (LAG3), and the Fgl1-LAG3 interaction is involved in immune-related pathways, influencing immune cell infiltration, proliferation, and secretion [1,2,6,8]. It also participates in regulating iron metabolism by suppressing hepcidin through antagonizing BMP signaling [5]. In addition, it has implications in cell proliferation, metabolism, and is associated with various disease conditions [2].

In metastatic colorectal cancer, Fgl1 secreted from cancer cells and hepatocytes reduces T-cell infiltration, facilitating cancer progression. Disrupting the TAM-OTUD1-Fgl1 axis can inhibit metastatic tumor progression [3]. In non-small cell lung cancer (NSCLC), Fgl1 promotes tumor cell proliferation, migration, and invasion. High Fgl1 expression is associated with poor prognosis, and its dynamic change on circulating tumor cells can be a biomarker for treatment efficacy prediction. Also, Fgl1 confers gefitinib resistance in NSCLC cell lines by regulating the PARP1/caspase 3 pathway [4,7]. In mice, deletion of Fgl1 leads to higher hepcidin levels at baseline and after bleeding, highlighting its role in iron metabolism regulation [5]. In systemic lupus erythematosus (SLE) with liver damage, Fgl1 is up-regulated, and the Fgl1-LAG3 axis impairs regulatory T cell function associated with disease activity [8].

In conclusion, Fgl1 is involved in important biological functions such as immune regulation, iron metabolism, and cell proliferation. Gene-knockout mouse models have revealed its role in diseases like cancer, iron-related disorders, and autoimmune diseases. Understanding Fgl1's functions through these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Shi, An-Ping, Tang, Xi-Yang, Xiong, Yan-Lu, Ma, Nan, Zhao, Jin-Bo. 2022. Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer. In Frontiers in immunology, 12, 785091. doi:10.3389/fimmu.2021.785091. https://pubmed.ncbi.nlm.nih.gov/35111155/

2. Qian, Wenjing, Zhao, Mingfang, Wang, Ruoyu, Li, Heming. 2021. Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target. In Journal of hematology & oncology, 14, 147. doi:10.1186/s13045-021-01161-8. https://pubmed.ncbi.nlm.nih.gov/34526102/

3. Li, Jia-Jun, Wang, Jin-Hong, Tian, Tian, Xu, Rui-Hua, Ju, Huai-Qiang. 2023. The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer. In Nature communications, 14, 6690. doi:10.1038/s41467-023-42332-0. https://pubmed.ncbi.nlm.nih.gov/37872170/

4. Sun, Cuilan, Gao, Weiwei, Liu, Jiatao, Cheng, Hao, Hao, Jiqing. 2020. FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer. In Respiratory research, 21, 210. doi:10.1186/s12931-020-01477-y. https://pubmed.ncbi.nlm.nih.gov/32778129/

5. Sardo, Ugo, Perrier, Prunelle, Cormier, Kevin, Ganz, Tomas, Kautz, Léon. . The hepatokine FGL1 regulates hepcidin and iron metabolism during anemia in mice by antagonizing BMP signaling. In Blood, 143, 1282-1292. doi:10.1182/blood.2023022724. https://pubmed.ncbi.nlm.nih.gov/38232308/

6. Wang, Jun, Sanmamed, Miguel F, Datar, Ila, Schalper, Kurt, Chen, Lieping. 2018. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. In Cell, 176, 334-347.e12. doi:10.1016/j.cell.2018.11.010. https://pubmed.ncbi.nlm.nih.gov/30580966/

7. Liu, Tian Yao, Yan, Jin Shan, Li, Xin, Zhao, Yue, Zhao, Ming Fang. 2024. FGL1: a novel biomarker and target for non-small cell lung cancer, promoting tumor progression and metastasis through KDM4A/STAT3 transcription mechanism. In Journal of experimental & clinical cancer research : CR, 43, 213. doi:10.1186/s13046-024-03140-6. https://pubmed.ncbi.nlm.nih.gov/39085849/

8. Chen, Kang, Li, Xingyu, Shang, Yuqi, Ming, Siqi, Wu, Yongjian. 2023. FGL1-LAG3 axis impairs IL-10-Producing regulatory T cells associated with Systemic lupus erythematosus disease activity. In Heliyon, 9, e20806. doi:10.1016/j.heliyon.2023.e20806. https://pubmed.ncbi.nlm.nih.gov/37916085/