Fgl1, or fibrinogen-like protein 1, is a protein secreted mainly by the liver. It is involved in multiple biological functions including regulating hepcidin and iron metabolism by antagonizing BMP signaling during anemia recovery in mice [5]. It also plays a crucial role in the immune system as a ligand of lymphocyte activation gene 3 (LAG3), and their interaction is associated with immune cell infiltration, proliferation, and secretion [1,2,6]. In addition, Fgl1 is related to cell proliferation and metabolism, and its expression is linked to various diseases, especially cancers [2].

In metastatic colorectal cancer, Fgl1 secreted from cancer cells and hepatocytes reduces T-cell infiltration, facilitating tumor progression. Disrupting the TAM-OTUD1-FGL1 axis, which upregulates FGL1 stability, inhibits metastatic tumor progression [3]. In non-small cell lung cancer (NSCLC), high FGL1 expression confers resistance to EGFR-TKI and gefitinib, and FGL1 knockdown enhances apoptosis induced by gefitinib [1,4]. Also, in NSCLC, Fgl1 promotes tumor cell proliferation, migration, and invasion through the KDM4A/STAT3 transcription mechanism, and its dynamic expression changes on circulating tumor cells can be a biomarker for predicting treatment efficacy [7]. In systemic lupus erythematosus (SLE) with liver damage, up-regulated Fgl1 from the injured liver, through the FGL1-LAG3 axis, impairs the suppressive function of regulatory T cells [8].

In conclusion, Fgl1 is a multifunctional protein involved in iron metabolism, immune regulation, and cancer progression. Mouse models, especially those disrupting relevant axes like the TAM-OTUD1-FGL1 axis in cancer, have revealed its role in disease development. These findings suggest that targeting Fgl1 could be a potential therapeutic strategy for various diseases, including cancers and SLE-related liver damage.

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/