Integrative Multi-Omics Reveal Metabolic Reprogramming by Ketogenic Diet in Melanoma Xenografts
The ketogenic diet (KD) has demonstrated anti-proliferative effects across multiple tumor types, yet the underlying metabolic and transcriptomic mechanisms remain incompletely understood. This study employed integrated multi-omics analysis combining targeted metabolomics and RNA-sequencing to elucidate KD-induced metabolic reprogramming in BRAF/NRAS wild-type, BRAF mutant, and NRAS mutant melanoma xenografts, which showed delayed tumor growth when treated with KD. Despite pronounced metabolic and transcriptional heterogeneity across models with minimal overlap in individual KD-responsive genes, pathway-level analysis revealed convergent biological signatures. Using correlation-based integration and supervised latent variable modeling (mixOmics DIABLO), we identified consistent KD-associated alterations in cancer-related pathways including PI3K-Akt and MAPK signaling, as well as sphingolipid, HIF-1, and shigellosis pathways. Mechanistically, KD enhanced sphingomyelin and ceramide levels in addition to the expression of ceramide synthesis genes while reducing ceramide breakdown. Moreover, KD induced downregulation of critical tumor regulators including PI3K, AKT, HIF, MEK, and ERK. These findings demonstrate that despite metabolic and transcriptomic heterogeneity, KD drives coordinated metabolic reprogramming at the pathway level, shifting lipid metabolism toward pro-apoptotic ceramides and attenuating key oncogenic signaling cascades. Our results provide mechanistic insights into KD's anti-tumor efficacy and identify metabolic nodes amenable to therapeutic intervention in melanoma.
The ketogenic diet (KD) has demonstrated anti-proliferative effects across multiple tumor types, yet the underlying metabolic and transcriptomic mechanisms remain incompletely understood. This study employed integrated multi-omics analysis combining targeted metabolomics and RNA-sequencing to elucidate KD-induced metabolic reprogramming in BRAF/NRAS wild-type, BRAF mutant, and NRAS mutant melanoma xenografts, which showed delayed tumor growth when treated with KD. Despite pronounced metabolic and transcriptional heterogeneity across models with minimal overlap in individual KD-responsive genes, pathway-level analysis revealed convergent biological signatures. Using correlation-based integration and supervised latent variable modeling (mixOmics DIABLO), we identified consistent KD-associated alterations in cancer-related pathways including PI3K-Akt and MAPK signaling, as well as sphingolipid, HIF-1, and shigellosis pathways. Mechanistically, KD enhanced sphingomyelin and ceramide levels in addition to the expression of ceramide synthesis genes while reducing ceramide breakdown. Moreover, KD induced downregulation of critical tumor regulators including PI3K, AKT, HIF, MEK, and ERK. These findings demonstrate that despite metabolic and transcriptomic heterogeneity, KD drives coordinated metabolic reprogramming at the pathway level, shifting lipid metabolism toward pro-apoptotic ceramides and attenuating key oncogenic signaling cascades. Our results provide mechanistic insights into KD's anti-tumor efficacy and identify metabolic nodes amenable to therapeutic intervention in melanoma.