Ffar4, also known as G protein-coupled receptor 120, is a long-chain fatty acid receptor belonging to the rhodopsin-like G protein-coupled receptor (GPCR) family. It plays a crucial role in maintaining energy homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. It is involved in pathways such as Gq subunit-mediated CaMKKβ/AMPK signaling, and its activation helps maintain metabolic homeostasis [2,4,6,7].

Systemic and conditional knockout mouse models have provided valuable insights into Ffar4's function. In acute kidney injury (AKI) mouse models, knockout of Ffar4 aggravated renal function and pathological damage, while activation by TUG-891 alleviated disease severity. Ffar4 was found to regulate cellular senescence in injured kidneys and tubular epithelial cells via the AMPK/SirT3 signaling pathway [1]. In metabolic syndrome (MetS) mouse models, conventional and microglial conditional knockout of Ffar4 exacerbated high-fat diet-induced cognitive dysfunction and anxiety, while microglial overexpression improved these conditions, with Ffar4 regulating microglial activation through type I interferon signaling [3]. In heart failure with preserved ejection fraction secondary to metabolic syndrome (HFpEF-MetS) mouse models, systemic deletion of Ffar4 worsened diastolic function and microvascular rarefaction in male mice, and altered the balance of inflammatory oxylipins, increasing the pro-inflammatory state [5].

In conclusion, Ffar4 is essential for maintaining metabolic and immune homeostasis. The use of Ffar4 knockout and conditional knockout mouse models has revealed its significance in diseases such as AKI, MetS-related cognitive impairment, and HFpEF-MetS. These findings suggest that Ffar4 could be a potential therapeutic target for treating these and other related diseases.