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Hepatocellular carcinoma is an aggressive cancer characterized by metabolic reprogramming in lipid-, nucleotide and amino acid metabolism/catabolism and oxidative stress management. This in vitro study investigates the potential cytotoxic and metabolic effects of the novel combination of doxorubicin and atorvastatin, a cholesterol-lowering drug, in the well-characterized Huh-7 cell line. The cytotoxicity of statins and fibrates was assessed through dose-response curves and the half-maximal inhibitory concentration (IC50) for each treatment, both individually and in combination. Synergism was determined using the Chou-Talalay method. Among the tested agents, atorvastatin exhibited the most potent cytotoxicity, with an IC50 of 70.45 µM. When combined with doxorubicin, the IC50 of doxorubicin decreased significantly from 165.25 µM to 26.85 µM, indicating a synergistic effect. Metabolic profiling revealed distinct changes in lipid metabolism, fatty acid oxidation and the carnitine shuttle system, specifically within the combination treatment. The combination treatment also seems to affect oxidative stress management via the urea cycle, polyamine biosynthesis, and catabolism of nucleotides and amino acids. By limiting energy production, while simultaneously disrupting oxidative stress management, this therapy creates a plausible metabolic bottleneck, which may impair cancer cell adaptation to stress and growth. These findings suggest that combining atorvastatin with doxorubicin might enhance treatment efficacy and/or reduce resistance.