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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 the 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 VIP score-based integration and supervised latent variable modeling (mixOmics DIABLO), we identified consistent KD-associated alterations in cancer-related pathways including the PI3K-Akt, MAPK, sphingolipid as well as HIF-1 signaling pathways. The KD enhanced sphingomyelin and ceramide levels and additionally induced transcriptional signatures, indicating increased ceramide synthesis and reduced ceramide breakdown. Moreover, the KD reduced transcript levels of genes encoding critical tumor regulators, including PI3K, AKT, HIF, MEK, and ERK. These findings demonstrate that despite metabolic and transcriptomic heterogeneity, the KD drives coordinated metabolic reprogramming at the pathway level, indicative of shifting lipid metabolism toward pro-apoptotic ceramides and attenuating key oncogenic signaling cascades. Our results provide insights into the KD\u2019s anti-tumor efficacy and identify metabolic nodes amenable to therapeutic intervention in melanoma.<\/jats:p>","DOI":"10.3390\/biom16071071","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T13:25:46Z","timestamp":1784726746000},"page":"1071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Multi-Omics Reveal Metabolic Reprogramming by Ketogenic Diet in Melanoma Xenografts"],"prefix":"10.3390","volume":"16","author":[{"given":"Rohit","family":"Dnyansagar","sequence":"first","affiliation":[{"name":"Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical Private University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9505-6271","authenticated-orcid":false,"given":"Natalie","family":"Bordag","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5195-5155","authenticated-orcid":false,"given":"Rodolphe","family":"Poupardin","sequence":"additional","affiliation":[{"name":"Cell Therapy Institute, Paracelsus Medical Private University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0195-2619","authenticated-orcid":false,"given":"Julia","family":"Tevini","sequence":"additional","affiliation":[{"name":"Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical Private University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6388-3766","authenticated-orcid":false,"given":"Victoria E.","family":"Stefan","sequence":"additional","affiliation":[{"name":"Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical Private University, 5020 Salzburg, Austria"},{"name":"Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Derdak","sequence":"additional","affiliation":[{"name":"Core Facilities, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Bilban","sequence":"additional","affiliation":[{"name":"Core Facilities, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Fortelny","sequence":"additional","affiliation":[{"name":"Center for Tumor Biology and Immunology, Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1198-4776","authenticated-orcid":false,"given":"Barbara","family":"Kofler","sequence":"additional","affiliation":[{"name":"Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical Private University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9750-0188","authenticated-orcid":false,"given":"Roland","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical Private University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9825-6674","authenticated-orcid":false,"given":"Daniela D.","family":"Weber","sequence":"additional","affiliation":[{"name":"Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical Private University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.molmed.2014.12.007","article-title":"Molecular drivers of cellular metabolic reprogramming in melanoma","volume":"21","author":"Abildgaard","year":"2015","journal-title":"Trends Mol. 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