FOXK1 and FOXK2 Orchestrate Transcriptional Networks Linking Insulin Signalling, Metabolic Reprogramming, and Mitochondrial Function
Abstract
Sonu Kumar, Ankit Kumar Rai and Sandeep Kumar
Insulin signalling coordinates cellular metabolism, growth, energy utilization, and adaptation to nutrient availability through interconnected kinase and transcriptional networks. Although FOXO transcription factors are well-established mediators of insulin-dependent transcriptional repression, increasing evidence identifies the forkhead transcription factors FOXK1 and FOXK2 as complementary nutrient-responsive regulators that integrate insulin signaling with metabolic and mitochondrial adaptation. FOXK1 and FOXK2 are regulated by insulin- and nutrient-sensitive signaling pathways involving AKT, mTORC1, and glycogen synthase kinase-3, resulting in changes in their subcellular localization, transcriptional activity, and downstream metabolic programs. Experimental studies indicate that FOXK1/FOXK2 regulate aerobic glycolysis, glucose utilization, lipid metabolism, mitochondrial respiration, and cellular proliferation. FOXK1 has particularly strong evidence for participation in hepatic insulin-responsive transcription, including direct occupancy of promoters and enhancers associated with metabolic and cellular programs. In parallel, FOXK1 contributes to mTORC1-dependent metabolic reprogramming through GSK3- and HIF1α-associated mechanisms. FOXK2 has emerging and context-dependent roles in mitochondrial bioenergetics and lipid metabolic remodeling, including regulation of fatty-acid oxidation and the mTOR/DRP1 axis in cancer models. Nutrient-sensitive post-translational mechanisms further expand FOXK function, as demonstrated by O-GlcNAcylation-dependent regulation of FOXK1, BAP1 recruitment, and E2F-associated proliferative transcription. Collectively, these findings support a model in which FOXK1 and FOXK2 act as partially overlapping but functionally specialized transcriptional integrators that coordinate glucose and lipid utilization with mitochondrial activity and cellular growth. Their biological effects are highly context dependent and vary according to tissue, nutrient status, signaling environment, transcriptional cofactors, and post- translational regulation. Despite substantial mechanistic progress, important questions remain regarding FOXK1/ FOXK2 target specificity, tissue-specific functions, human genetic and clinical relevance, and the causal relationship between FOXK activity and metabolic disease. Integrated approaches combining genetic perturbation, transcriptomics, chromatin profiling, proteomics, phosphoproteomics, O-GlcNAc proteomics, metabolomics, metabolic-flux analysis, mitochondrial phenotyping, and human tissue validation will be required to define the FOXK regulatory network more precisely. FOXK1 and FOXK2 therefore represent promising biological nodes for understanding the intersection of insulin signaling, metabolic reprogramming, mitochondrial function, and disease progression, while their potential as therapeutic targets remains investigational.