Abstract
Background/Objectives: Melanoma is an aggressive skin cancer with intratumor metabolic heterogeneity, which drives its progression and therapy resistance. Natural anthraquinones, such as emodin and aloe-emodin, exhibit anti-cancer properties, but their effects on metabolic plasticity remain unclear. This study evaluated their impact on proliferation and metabolic pathways in heterogenous melanoma human cell lines. Methods: COLO 800, COLO 794, and A375 melanoma cell lines representing distinct metabolic phenotypes were analyzed. Targeted and untargeted metabolomics analyses integrated with Seahorse assays were performed to assess the effects of emodin and aloe-emodin on cell proliferation, mitochondrial function, and redox homeostasis. Glucose tracing using [U-(13)C(6)] glucose and metabolic flux analysis (MFA) were carried out to evaluate the glycolysis and TCA cycle dynamics. Results: Emodin and aloe-emodin inhibited proliferation by disrupting glycolysis, oxidative phosphorylation, and energy production across all cell lines. Both compounds impaired glucose metabolism, reduced TCA cycle intermediates, and induced mitochondrial ROS accumulation, causing oxidative stress and redox imbalance. Despite intrinsic metabolic differences, COLO 800 and COLO 794 upregulated antioxidant defenses; A375 enhanced one-carbon metabolism and amino acid pathways to maintain redox balance and nucleotide biosynthesis. Conclusions: Emodin and aloe-emodin can disrupt the metabolic plasticity of melanoma cells by impairing glycolysis, mitochondrial function, and redox homeostasis. Their ability to target metabolic vulnerabilities across diverse phenotypes highlights their therapeutic potential for overcoming resistance mechanisms and advancing melanoma treatment strategies.