GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism.

Liver cancer, primary hepatocellular carcinoma (HCC), posing a significant threat to human health due to its high prevalence and limited treatment options. As a first-line chemotherapeutic agent for HCC, 5-fluorouracil (5-FU) has demonstrated significant efficacy in suppressing tumor cell proliferation through its cytotoxic mechanisms. Yet, prolonged 5-FU administration often induces chemo-resistant phenotypes in cancer cells, severely compromising the long-term efficacy of 5-FU-based treatment regimens and becoming a major barrier to successful HCC therapy. In this study, we investigated the mechanism underlying 5-FU resistance in Bel7402 hepatoma cells and found that it is closely related to metabolic reprogramming of glutamine. Notably, we demonstrated that CB-839, which is an inhibitor of glutamine metabolism's rate-limiting enzyme (glutaminase), has no notable anti-tumor activity alone but effectively enhances resistant HCC cells' sensitivity to 5-FU both in vitro and in vivo. The mechanism underlying this sensitization involves the disruption of cellular redox homeostasis. Specifically, the combination of CB-839 and 5-FU increases the accumulation of reactive oxygen species (ROS) and induces oxidative stress by consuming intracellular glutathione (GSH) reserves. Furthermore, this combination therapy elevates intracellular Fe2+levels and promotes lipid peroxidation, ultimately triggering ferroptosis. Collectively, these findings tentatively address certain aspects of the unclear mechanism underlying 5-FU resistance in HCC. Specifically, they may suggest targeting glutamine metabolism as a potential avenue for intervention and offer novel perspectives on understanding this resistance. Concurrently, these discoveries provide some support for optimizing chemotherapy regimens, with the aim of surmounting the current clinical challenges in reversing drug resistance.