FSTL3, or follistatin-like 3, is a cytokine that can regulate insulin sensitivity and counteract activin/myostatin signalling [9]. It is also involved in various biological processes, including inflammation, lipid metabolism, and cell-cycle regulation. It may modulate target gene expression via members of the transforming growth factor β (TGF-β) superfamily [7]. Genetic models, such as gene knockout (KO) mouse models, could potentially help in further understanding its functions.

In type 2 diabetes mellitus (T2DM) patients, increased non-alcoholic fatty liver disease (NAFLD) fibrosis risk was associated with acute myocardial infarction (AMI), and serum FSTL3 partially mediated this association. FSTL3 expression was enriched in the liver of NAFLD patients with significant and advanced fibrosis [1]. In colorectal cancer, FSTL3 promoted tumor immune evasion and attenuated response to anti-PD1 therapy by stabilizing c-Myc. Hypoxic tumor microenvironment induced FSTL3 expression via HIF1α, and FSTL3 up-regulated the expression of PDL1 and IDO1 [2]. In overweight or obese individuals, FSTL3 was highly expressed in adipose tissue and could suppress adipocyte inflammation. Serum FSTL3 levels might be considered as a biomarker of visceral obesity and inflammation [3]. In lung adenocarcinoma, FSTL3 expression was reduced, and it was significantly associated with prognosis, progression, and immune cell infiltration [4]. FSTL3-neutralizing antibodies enhanced glucose-responsive insulin secretion in dysfunctional male mouse and human islets, suggesting a potential therapeutic strategy for diabetes [5]. In macrophages, FSTL3 induced lipid accumulation and inflammatory response, and was associated with atherosclerosis [6]. In gastric cancer, FSTL3 was up-regulated, linked to cancer stage and pathological grade, and associated with a poor survival duration. FSTL3 overexpression could activate epithelial-mesenchymal transition (EMT) and promote the proliferation of M2 tumor-associated macrophages (TAMs) [7]. In pulmonary arterial hypertension (PAH), both baseline and follow-up serum levels of FSTL3 were associated with transplant-free survival, and histological analyses showed higher immunoreactivity for FSTL3 in vascular endothelial and smooth muscle layers [8]. In renal dysfunction, circulating FSTL3 was significantly and independently associated with renal function, and hepatic mFSTL3 mRNA up-regulation might contribute to increased FSTL3 levels [9]. In hepatocellular carcinoma (HCC), FSTL3 was predominantly expressed in stromal components and was a factor in enhancing fibroblast-M2 macrophage signalling crosstalk, related to the pathogenesis of HCC and immunotherapy resistance [10].

In conclusion, FSTL3 is involved in a wide range of biological functions and diseases. Studies using mouse models, such as KO mouse models, would potentially contribute to a better understanding of its role in these disease areas, including diabetes-related liver and heart diseases, cancer, obesity, and cardiovascular and renal diseases.

References:

1. Duan, Wenfei, Shi, Ruixiao, Yang, Fang, Huang, Zhe, Zang, Shufei. 2023. FSTL3 partially mediates the association of increased nonalcoholic fatty liver disease fibrosis risk with acute myocardial infarction in patients with type 2 diabetes mellitus. In Cardiovascular diabetology, 22, 297. doi:10.1186/s12933-023-02024-x. https://pubmed.ncbi.nlm.nih.gov/37904173/

2. Li, Haiyang, Zheng, Na, Guo, Anning, Wang, Hanjin, Zhao, Shuli. 2024. FSTL3 promotes tumor immune evasion and attenuates response to anti-PD1 therapy by stabilizing c-Myc in colorectal cancer. In Cell death & disease, 15, 107. doi:10.1038/s41419-024-06469-0. https://pubmed.ncbi.nlm.nih.gov/38302412/

3. Li, Xiaoya, Zhang, Hongwei, Ma, Xiaojing, Yu, Haoyong, Bao, Yuqian. 2022. FSTL3 is highly expressed in adipose tissue of individuals with overweight or obesity and is associated with inflammation. In Obesity (Silver Spring, Md.), 31, 171-183. doi:10.1002/oby.23598. https://pubmed.ncbi.nlm.nih.gov/36502285/

4. Meng, Xiangzhi, Zhao, Xiaojian, Zhou, Boxuan, Shi, Jianwei, Gao, Yushun. 2024. FSTL3 is associated with prognosis and immune cell infiltration in lung adenocarcinoma. In Journal of cancer research and clinical oncology, 150, 17. doi:10.1007/s00432-023-05553-w. https://pubmed.ncbi.nlm.nih.gov/38240936/

5. Brown, Melissa L, Lopez, Alexa, Meyer, Nolan, Richter, Alden, Thompson, Thomas B. . FSTL3-Neutralizing Antibodies Enhance Glucose-Responsive Insulin Secretion in Dysfunctional Male Mouse and Human Islets. In Endocrinology, 162, . doi:10.1210/endocr/bqab019. https://pubmed.ncbi.nlm.nih.gov/33539535/

6. Runhua, Ma, Qiang, Ji, Yunqing, Shi, Wenjun, Ding, Chunsheng, Wang. . FSTL3 Induces Lipid Accumulation and Inflammatory Response in Macrophages and Associates With Atherosclerosis. In Journal of cardiovascular pharmacology, 74, 566-573. doi:10.1097/FJC.0000000000000742. https://pubmed.ncbi.nlm.nih.gov/31815869/

7. Liu, Yuan-Jie, Li, Jie-Pin, Zhang, Ying, Liu, Shen-Lin, Zou, Xi. 2021. FSTL3 is a Prognostic Biomarker in Gastric Cancer and is Correlated with M2 Macrophage Infiltration. In OncoTargets and therapy, 14, 4099-4117. doi:10.2147/OTT.S314561. https://pubmed.ncbi.nlm.nih.gov/34262295/

8. Guignabert, Christophe, Savale, Laurent, Boucly, Athénaïs, Sitbon, Olivier, Humbert, Marc. 2023. Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension. In Circulation, 147, 1809-1822. doi:10.1161/CIRCULATIONAHA.122.061501. https://pubmed.ncbi.nlm.nih.gov/37096577/

9. Kralisch, Susan, Hoffmann, Annett, Klöting, Nora, Fasshauer, Mathias, Ebert, Thomas. . FSTL3 is increased in renal dysfunction. In Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 32, 1637-1644. doi:10.1093/ndt/gfw472. https://pubmed.ncbi.nlm.nih.gov/28339962/

10. Li, Jie-Pin, Liu, Yuan-Jie, Yin, Yi, Huang, Wei, Zou, Xi. 2023. Stroma-associated FSTL3 is a factor of calcium channel-derived tumor fibrosis. In Scientific reports, 13, 21317. doi:10.1038/s41598-023-48574-8. https://pubmed.ncbi.nlm.nih.gov/38044354/