Role of FOXO3a Transcription Factor in the Regulation of Liver Oxidative Injury

Abstract

Oxidative stress has been identified as a key mechanism in liver damage caused by various chemicals. The transcription factor FOXO3a has emerged as a critical regulator of redox imbalance. Multiple post-translational changes and epigenetic processes closely regulate the activity of FOXO3a, resulting in synergistic or competing impacts on its subcellular localization, stability, protein-protein interactions, DNA binding affinity, and transcriptional programs. Depending on the chemical nature and subcellular context, the oxidative-stress-mediated activation of FOXO3a can induce multiple transcriptional programs that play crucial roles in oxidative injury to the liver by chemicals. Here, we mainly review the role of FOXO3a in coordinating programs of genes that are essential for cellular homeostasis, with an emphasis on exploring the regulatory mechanisms and potential application of FOXO3a as a therapeutic target to prevent and treat liver oxidative injury.

Keywords: FOXO3a transcription factor; cell death; cell survival; liver injury; mitochondria; oxidative stress.

Figure 1

Reactive intermediate species metabolism induces oxidative stress in the liver. Liver oxidative injury is initiated by free radicals produced by metabolic conversion of chemicals into reactive intermediate species (red color), such as electrophilic compounds and ROS. Superoxide (O₂^•−) is generated as a by-product during oxidative phosphorylation within mitochondria. Superoxide can be converted to H₂O₂ by SOD enzymes. H₂O₂ is then scavenged by antioxidant enzymes such as GPx and catalase. ETC, electron-transport chain complexes; GPx, glutathione peroxidase; NQO1, NAD(P)H quinone oxidoreductase 1; SOD, superoxide dismutase.

Figure 2

FOXO3a structure and its post-translational modifications to regulate liver oxidative injury. (A) Human FOXO3a domains. CR1–CR3, conserved regions 1–3; DBD: DNA-binding domain; NLS: nuclear localization signal domain; NES: nuclear export sequence; TAD, transactivation domain. (B) Major PTMs residues of FOXO3a regulated by various xenobiotics. In response to oxidative stress, FOXO3a undergoes PTMs in the NLS and NES domains, which affects its subcellular localization, stability, protein–protein interactions, and the transcriptional activity and specificity.

Figure 3

Epigenetic regulation of FOXO3a via microRNAs and histone modifications. (A). Diverse miRNAs are identified which regulate FOXO3a directly or indirectly upon oxidative stress. (B). Involvement of histone modifications in the control of FOXO3a transactivation in response to environmental factors. FOXO3a is responsible for autophagy gene expression by influencing chromatin structure through decrease in SKP2 to up-regulate CARM1, the CARM1–Pontin–FOXO3a signaling axis works for enhancer activation to establish target gene regulation by increasing H4 acetylation. Additionally, modification of histone H1 through PARylation by stimulation of PARP1 dissociates histone H1 from DNA, exposing the autophagy gene promoter regions and enhancing FOXO3a binding to the target gene promoters through epigenetic reprogramming of FOXO3a transactivation. CARM1: coactivator-associated arginine methyltransferase 1.

Figure 3

Epigenetic regulation of FOXO3a via microRNAs and histone modifications. (A). Diverse miRNAs are identified which regulate FOXO3a directly or indirectly upon oxidative stress. (B). Involvement of histone modifications in the control of FOXO3a transactivation in response to environmental factors. FOXO3a is responsible for autophagy gene expression by influencing chromatin structure through decrease in SKP2 to up-regulate CARM1, the CARM1–Pontin–FOXO3a signaling axis works for enhancer activation to establish target gene regulation by increasing H4 acetylation. Additionally, modification of histone H1 through PARylation by stimulation of PARP1 dissociates histone H1 from DNA, exposing the autophagy gene promoter regions and enhancing FOXO3a binding to the target gene promoters through epigenetic reprogramming of FOXO3a transactivation. CARM1: coactivator-associated arginine methyltransferase 1.

Figure 4

Proposed schematic representation of FOXO3a-mediated stress response in the liver. FOXO3a orchestrates multiple transcriptional programs to regulate apoptosis, ROS detoxification, and autophagy (arrows indicate active functions, and bar-headed lines represent inhibitory effects).