KLF16-induced Increase of GARS Promotes Glycolysis in Hepatocellular Carcinoma by Stabilizing FOXK1

Reprogramming of glucose metabolism is a hallmark of hepatocellular carcinoma (HCC); however, the intrinsic mechanisms underlying this phenomenon remain unclear. The present study aimed to investigate the role and potential mechanism of glycyl-tRNA synthetase (GARS) in HCC glycolysis. Our results revealed an increase in the expression of Kruppel-like factor 16 (KLF16) and forkhead box K1 (FOXK1) in HCC tissues and correlated with an unfavorable prognosis. Mechanistically, we demonstrated that KLF16 binds to the promoter region of GARS, thereby enhancing its transcription. Subsequently, the GARS protein then binds to FOXK1, resulting in reduced ubiquitination and increased stability of FOXK1. FOXK1 then promotes glycolysis by directly stimulating the transcription of lactate dehydrogenase A, pyruvate kinase M2 and glucose transporter 1 in HCC cells. Additionally, KLF16 knockdown inhibited glycolysis in HCCLM3 cells both in vitro and in vivo. Collectively, these findings indicate that the KLF16-GARS-FOXK1 axis plays a critical role in regulating HCC growth and glycolysis. Targeting this pathway may hold a promising therapeutic strategy for HCC treatment.