Fstl1, also known as follistatin-related protein 1 or follistatin-like protein 1, is a secreted glycoprotein involved in many physiological functions [2]. It has been implicated in various signaling pathways such as TGF-β/BMP/Smad, AKT, NF-κB, and Wnt-β-catenin signaling pathways [2]. Fstl1 is of great biological importance as it participates in processes like angiogenesis, cell proliferation, and differentiation, and is associated with numerous diseases including fibrosis, cancer, and osteoarthritis [2,3,5]. Genetic models, especially knockout (KO) mouse models, have been crucial in understanding its functions.

In liver fibrosis, myeloid-specific Fstl1-knockout (Fstl1M-KO) mice showed attenuated fibrosis progression, reduced inflammation, and suppressed pro-inflammatory M1 macrophage polarization. Fstl1 was found to bind to pyruvate kinase M2 (PKM2), promoting its phosphorylation and nuclear translocation to enhance PKM2-dependent glycolysis and M1 polarization [1]. In non-alcoholic steatohepatitis, skeletal muscle specific IRF4 knockout (F4MKO) mice with ameliorated liver pathology had altered Fstl1 levels, indicating a link between muscles and the liver through the IRF4-Fstl1-DIP2A/CD14 pathway [4]. In osteosarcoma, Fstl1 knockout in OS cells suppressed cellular functions and led to the generation of potent NK cells, suggesting that blocking Fstl1 could be a promising treatment strategy [6].

In conclusion, Fstl1 is a multifunctional protein involved in key biological processes. KO mouse models have been instrumental in revealing its role in diseases such as liver fibrosis, non-alcoholic steatohepatitis, and osteosarcoma. Understanding Fstl1's functions through these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Rao, Jianhua, Wang, Hao, Ni, Ming, Cheng, Feng, Lu, Ling. 2022. FSTL1 promotes liver fibrosis by reprogramming macrophage function through modulating the intracellular function of PKM2. In Gut, 71, 2539-2550. doi:10.1136/gutjnl-2021-325150. https://pubmed.ncbi.nlm.nih.gov/35140065/

2. Du, Ruijuan, Li, Kai, Guo, Kelei, Han, Li, Bian, Hua. 2024. FSTL1: A double-edged sword in cancer development. In Gene, 906, 148263. doi:10.1016/j.gene.2024.148263. https://pubmed.ncbi.nlm.nih.gov/38346455/

3. Li, Wencui, Alahdal, Murad, Deng, Zhiqin, Tang, Kanglai, Zhang, Jiqiang. 2020. Molecular functions of FSTL1 in the osteoarthritis. In International immunopharmacology, 83, 106465. doi:10.1016/j.intimp.2020.106465. https://pubmed.ncbi.nlm.nih.gov/32259701/

4. Guo, Shanshan, Feng, Yonghao, Zhu, Xiaopeng, Gao, Huanqing, Kong, Xingxing. 2023. Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis. In Nature communications, 14, 6047. doi:10.1038/s41467-023-41832-3. https://pubmed.ncbi.nlm.nih.gov/37770480/

5. Li, Xiaohe, Fang, Yinshan, Jiang, Dingyuan, Jiang, Dianhua, Ning, Wen. 2020. Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases. In Molecular therapy : the journal of the American Society of Gene Therapy, 29, 347-364. doi:10.1016/j.ymthe.2020.09.031. https://pubmed.ncbi.nlm.nih.gov/33007201/

6. Ogiwara, Yamato, Nakagawa, Makoto, Nakatani, Fumihiko, Zhang, Rong, Kudo-Saito, Chie. 2022. Blocking FSTL1 boosts NK immunity in treatment of osteosarcoma. In Cancer letters, 537, 215690. doi:10.1016/j.canlet.2022.215690. https://pubmed.ncbi.nlm.nih.gov/35439537/