STF31 Targeting GLUT1 in VHLDeficient Clear Cell Renal Cell Carcinoma

VHL gene is a typical gene that is frequently mutated in clear cell renal cell carcinoma (ccRCC). It can promote the expression of glucose transporter 1 (GLUT1) and the Warburg effect by stabilizing hypoxia-inducible factor 1α (HIF-1α) to induce glycolytic dependence in tumour cells. Targeted Therapy to address the metabolic weakness can also be used. Systematically review the metabolic regulatory mechanism of HIF-1α/GLUT1 in VHL-inactivation and summarize the anti-tumour effects and potential applications of the selective GLUT1 inhibitor STF-31. Studies have shown that VHL dysfunction leads to the continuous accumulation of HIF-1α, which upregulates GLUT1 and glycolysis-related genes, thus promoting a state of persistent aerobic glycolysis in ccRCC cells. High expression of GLUT1 is associated with enhanced tumour invasion and a poor prognosis. STF-31 can selectively inhibit GLUT1-mediated glucose uptake to cause energy metabolism disorders, and it preferentially inhibits VHL-deficient tumour cells via synthetic lethality. Previous in vitro and animal studies have also shown that STF-31 is good at inhibiting cancer and is relatively non-toxic to normal cells. The metabolic axis of VHL-HIF-1α-GLUT1 is a potential therapeutic target for ccRCC, and STF-31 has proposed a new research direction in metabolic-targeted therapy of VHL-deficient tumours. In the future, research will be conducted to further optimise the pharmacokinetics and drug-delivery properties of STF-31, explore combination strategies with immunotherapy and anti-angiogenic therapy, and carry out clinical trials to evaluate its efficacy and safety in patients before use in patients.