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Brain metastases (BM) affect 20\u201330% of cancer patients, primarily originating from lung cancer, breast cancer, and melanoma. Despite advances in molecular-targeted therapies, brain metastatic disease remains incurable, with a poor median survival of \u226412 months if left untreated. The lack of therapeutic efficacy is mainly attributed to the presence of the blood\u2013brain barrier (BBB) and genetic differences between BM and their primary tumors. Previously published data have identified potential driver mutations of BM. However, the mechanisms underlying brain cancer dissemination remain unknown. Recent studies emphasize the pivotal role of metabolic adaptations in supporting the metastatic process, particularly in the nutrient-poor microenvironment characteristic of the brain. Understanding the interplay between metabolism and genetic alterations associated with brain metastatic disease could unveil novel therapeutic targets that are more effective in treating patients. This review focuses on relevant metabolic pathways in cancer, particularly brain cancer dissemination, while also presenting information on current preclinical models of BM, relevant clinical trials, and preclinical studies targeting metabolic reprogramming, providing an overview for advancing therapeutic strategies in BM.<\/jats:p>","DOI":"10.3390\/cells14100707","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T11:31:49Z","timestamp":1747135909000},"page":"707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unlocking the Role of Metabolic Pathways in Brain Metastatic Disease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1673-5676","authenticated-orcid":false,"given":"Madalena","family":"Pinto","sequence":"first","affiliation":[{"name":"GIMM\u2014Gulbenkian Institute for Molecular Medicine, Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Violante","sequence":"additional","affiliation":[{"name":"GIMM\u2014Gulbenkian Institute for Molecular Medicine, Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5533-9413","authenticated-orcid":false,"given":"Rita","family":"Casc\u00e3o","sequence":"additional","affiliation":[{"name":"GIMM\u2014Gulbenkian Institute for Molecular Medicine, Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia C.","family":"Faria","sequence":"additional","affiliation":[{"name":"GIMM\u2014Gulbenkian Institute for Molecular Medicine, Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal"},{"name":"Department of Neurosurgery, Hospital de Santa Maria, Unidade Local de Sa\u00fade de Santa Maria (ULSSM), Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal"},{"name":"Cl\u00ednica Universit\u00e1ria de Neurocirurgia, Faculdade de Medicina da Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mani, K., Deng, D., Lin, C., Wang, M., Hsu, M.L., and Zaorsky, N.G. 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