FoxO6, a member of the forkhead box O (FOXO) transcription factor family, has distinct regulatory mechanisms compared to other FOXO proteins, such as its inability to undergo classical nucleocytoplasmic shuttling [2]. It is involved in various physiological and pathological processes including apoptosis, oxidative stress, autophagy, cell cycle control, and inflammation [2]. FoxO6 also mediates insulin action on target genes in a unique way and is associated with insulin resistance, dietary obesity, type 2 diabetes, and neurodegeneration disease [1].

In aged rats fed a high-fat diet, FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia [3]. FoxO6-Tg mice showed increased ApoC3-driven lipid accumulation in the liver, leading to hepatic steatosis and hyperglycemia, while FoxO6-KO mice had attenuated lipogenesis gene expression, less hepatic lipid accumulation, and mitigated hyperlipidemia [3]. In another study, in mice overexpressing constitutively active FoxO6 allele, FoxO6 activation induced hepatic lipogenesis and ER stress-inducible genes, and interacted with CHOP to promote hepatic lipid accumulation through PPARγ expression [4].

In conclusion, FoxO6 plays a crucial role in glucose and lipid metabolism, as well as in processes related to inflammation and oxidative stress. Findings from FoxO6-KO and transgenic mouse models have revealed its contributions to the development of hepatic steatosis, hyperlipidemia, and hyperglycemia, suggesting its potential as a therapeutic target for metabolic diseases [3,4].