FOXK2 (forkhead box K2) is a transcriptional regulator that plays critical roles in metabolic reprogramming and cancer biology. FOXK2 functions as both a transcriptional activator and repressor by binding to forkhead DNA sequence motifs and regulating target gene expression 1. A key function is promoting aerobic glycolysis by upregulating glycolytic enzymes (hexokinase-2, phosphofructokinase, pyruvate kinase, lactate dehydrogenase) while simultaneously suppressing mitochondrial pyruvate oxidation through activation of pyruvate dehydrogenase kinases 1. FOXK2 also promotes nucleotide de novo synthesis by directly regulating nucleotide synthetic genes, with its nuclear translocation enhanced by PIAS4-mediated SUMOylation 2. In response to insulin signaling, FOXK2 translocates from cytoplasm to nucleus via the Akt-mTOR pathway, reciprocal to FoxO1 regulation 3. FOXK2 demonstrates significant oncogenic potential, being frequently amplified in breast cancer and contributing to tumorigenesis, chemotherapy resistance, and poor patient survival 4. Additionally, FOXK2 can be O-GlcNAcylated by OGT in response to ROS, facilitating its nuclear translocation and subsequent activation of SLC7A11 transcription, which inhibits ferroptosis and contributes to chemoradiotherapy resistance in hepatocellular carcinoma 5. FOXK2 also promotes cardiomyocyte proliferation and heart regeneration by activating cell cycle genes 6.