Ffar2, also known as GPR43, is a G-protein-coupled receptor activated by short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate. It is involved in multiple biological processes, including metabolism and immune regulation. FFAR2-mediated signaling pathways play a role in regulating the release of gut hormones, immune cell function, and gut homeostasis [3,4]. Gene knockout models have been crucial in understanding its function.

Whole or myeloid Ffar2 gene deletion in mouse models significantly inhibited urethane-induced lung carcinogenesis and syngeneic tumor growth. This was associated with reduced myeloid-derived suppressor cells (MDSCs) and increased CD8+ T cell infiltration. Mechanistically, FFAR2 deficiency in MDSCs decreased the expression of Arg1 through the Gαq/Calcium/PPAR-γ axis, relieving T cell dysfunction [1]. In ILC3-specific Ffar2-deficient mice, in situ proliferation of ILC3s and interleukin-22 production were decreased, leading to impaired gut epithelial function and increased susceptibility to colonic injury and bacterial infection [2].

In conclusion, Ffar2 is essential for maintaining gut immunity, regulating immune cell function in cancer, and controlling cell ferroptosis. Gene knockout mouse models have revealed its role in cancer immunoevasion, gut homeostasis, and susceptibility to infections, highlighting its potential as a therapeutic target for cancer, gut-related diseases, and infections [1-5].

References:

1. Zhao, Zeda, Qin, Juliang, Qian, Ying, Liu, Mingyao, Du, Bing. 2024. FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion. In Journal of hematology & oncology, 17, 9. doi:10.1186/s13045-024-01529-6. https://pubmed.ncbi.nlm.nih.gov/38402237/

2. Chun, Eunyoung, Lavoie, Sydney, Fonseca-Pereira, Diogo, Layden, Brian T, Garrett, Wendy S. 2019. Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity. In Immunity, 51, 871-884.e6. doi:10.1016/j.immuni.2019.09.014. https://pubmed.ncbi.nlm.nih.gov/31628054/

3. Tolhurst, Gwen, Heffron, Helen, Lam, Yu Shan, Reimann, Frank, Gribble, Fiona M. 2011. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. In Diabetes, 61, 364-71. doi:10.2337/db11-1019. https://pubmed.ncbi.nlm.nih.gov/22190648/

4. Kimura, Ikuo, Ichimura, Atsuhiko, Ohue-Kitano, Ryuji, Igarashi, Miki. 2019. Free Fatty Acid Receptors in Health and Disease. In Physiological reviews, 100, 171-210. doi:10.1152/physrev.00041.2018. https://pubmed.ncbi.nlm.nih.gov/31487233/