Esophageal squamous cell carcinoma (ESCC) remains an aggressive and lethal malignancy. Current therapies have limited efficacy due to local invasion and lymphatic metastasis, which are common with late-stage disease, highlighting the urgent need for second-line treatments. Dr. Qie’s research focuses on how ESCC cells respond to nutrient depletion, specifically glutamine withdrawal. Our previous study found the dysregulation of Fbxo4-cyclin D1 drives glutamine-addiction, a phenomenon defining highly proliferative cells that require glutamine for survival and proliferation. Mechanistically, Rb and mTORC1 are critical contributors to glutamine-addiction induced by dysregulated Fbxo4-cyclin D1 that drives mitochondrial deficiency and compromised energy production, finally, leading to the reprogramming of cellular metabolism. Taking advantage of this metabolic vulnerability, we found ESCC cells become sensitive to combined treatment with CB-839 (glutaminase 1 inhibitor) and metformin/phenformin in cell culture and in mouse xenografts. Our future research will focus on dissecting the detailed mechanism of how dysregulation of Fbxo4-cyclin D1 promotes glutamine uptake and utilization.