Blood Metabolites D-Lactate and Glycerol Reveal Who Benefits From Liver Cancer Drug

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and a leading cause of cancer death. Sorafenib, the first FDA-approved systemic therapy for advanced HCC, inhibits multiple kinases to block tumor growth and angiogenesis. However, most patients develop resistance within months, and no reliable plasma biomarkers currently exist to detect early treatment failure or guide therapeutic decisions.

This study used a p53−/−; Myc hepatoblast HCC cell model and sorafenib-resistant IR-Huh7 cells to systematically map how sorafenib alters cellular metabolism. The drug profoundly suppressed oxidative phosphorylation by disrupting electron transport chain (ETC) supercomplex assembly, reducing basal and maximal respiration, ATP production, and the activities of complexes I, II, and IV, while lowering mitochondrial membrane potential. This forced cells to increase reliance on glycolysis as their primary energy source.

Enhanced glycolysis generates dihydroxyacetone phosphate (DHAP), which can form harmful advanced glycation end-products (AGEs). In drug-sensitive cells, DHAP is converted to methylglyoxal (MG), detoxified via glyoxalase I and HAGH enzymes into D-lactate. D-lactate production, in turn, promotes ferroptosis—an iron-dependent form of cell death that contributes to sorafenib's therapeutic effect. In resistant cells, however, DHAP is preferentially channeled into glycerol-3-phosphate (G3P), fueling glycerolipid synthesis, regenerating NAD+, and remodeling membrane phospholipids by incorporating polyunsaturated fatty acids (PUFAs) in a controlled manner that limits lipid peroxidation. This membrane remodeling, combined with upregulated serine metabolism and enhanced glutathione synthesis, enables ferroptosis evasion. Excess glycerol generated from triglyceride breakdown is secreted extracellularly to maintain osmotic balance.

Critically, these mechanistic findings were validated in plasma samples from HCC patients receiving sorafenib. Patients who responded to treatment showed elevated plasma D-lactate, consistent with active glyoxalase-mediated detoxification and ferroptosis induction. In contrast, patients developing resistance exhibited elevated plasma glycerol, reflecting upregulated glycerolipid metabolism. Both metabolites were measurable in standard plasma samples, supporting their potential as accessible clinical biomarkers.

These findings reframe sorafenib resistance as a metabolic survival strategy centered on glycerolipid remodeling, antioxidant reinforcement, and ferroptosis escape. They open new avenues for combination therapies targeting these pathways and provide two simple plasma metabolite measurements—D-lactate and glycerol—that could guide real-time treatment monitoring in advanced HCC patients.