2) Hepatic Injury
The liver requires FOXOs to maintain cellular and metabolic balance, and
FOXO dysregulation may aid in the emergence of Non-alcoholic fatty liver
disease (NAFLD) (Dong., 2017). Given the significance of FOXOs in
maintaining healthy levels of lipids and glucose, it is not astonishing
that abnormalities in hepatic FOXO regulation might contribute to
metabolic ailments (Gross et al., 2009). AMP-activated protein kinase
(AMPK) plays a crucial function in hepatic metabolic regulation. Once
activated, AMPK inhibits energy-consuming biosynthesis processes, such
as fatty acid and sterol production, while simultaneously activating
ATP-producing catabolic pathways, including fatty acid oxidation and
activates autophagy in the liver (Viollet et al., 2006). FOXO3a
phosphorylation has been implicated as a key ROS-activated rapid
response. PI3K and the AMPK signalling pathway are the most important
sensors of stress signals in the management of FOXO3a-dependent cellular
homeostasis. In addition, it has been identified that the AMPK–FOXO3a
axis is the key homeostatic signalling framework that regulates the
physiological response to oxidative stress (Jin et al., 2022). In
addition to Akt/SGK, SIRT1, and PPAR-α, MAPK, an essential metabolic
master and cell energy sensor, has been implicated in influencing FOXO3a
transcriptional activity. SIRT1 and PPAR-α are reciprocally regulatory.
A rise in hepatic SIRT1 enhances PPAR-α activity, and PPAR-α is a
crucial factor in the upregulation of SIRT1 gene expression. PPAR-α is a
nuclear receptor that stimulates fatty acid oxidation, regulates lipid
metabolism, and stimulates autophagy (Gautam et al., 2020).