Abstract P26: Targeting Lactate-Induced Pyrimidine Biosynthesis Sensitizes Liver Cancer Cells to Ferroptosis

Abstract

Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy closely associated with the tumor microenvironment (TME), where stromal components significantly contribute to disease progression. Among these components, hepatic stellate cells (HSCs) play a pivotal role by responding to tumor-derived signals, leading to extracellular matrix (ECM) remodeling that facilitates tumor growth and invasion. Lactate, a major byproduct of aerobic glycolysis, functions not only as a metabolic substrate but also as a signaling molecule within the TME. However, its role in modulating ECM remodeling and resistance to ferroptosis remains poorly understood. In this study, we investigated how cancer-derived lactate influences ECM production in HSCs and contributes to resistance against sorafenib-induced ferroptosis in HCC. Our findings demonstrate that lactate enhances ECM deposition in HSCs through the activation of the mTORC1-dependent pyrimidine biosynthesis pathway, involving key enzymes such as CAD and dihydroorotate dehydrogenase (DHODH). This metabolic activation promotes pre-ribosomal RNA synthesis, thereby supporting the translation of ECM proteins. Consequently, ECM accumulation confers resistance to ferroptosis. Notably, pharmacological inhibition of DHODH suppresses ECM production and restores sensitivity to ferroptosis, underscoring the therapeutic potential of targeting this pathway. These results highlight a novel mechanism by which lactate promotes ECM remodeling and therapeutic resistance in HCC. Targeting the mTORC1–CAD–DHODH axis in HSCs may represent a promising strategy to overcome drug resistance and improve treatment outcomes in liver cancer.