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Hypoxia-inducible factor (HIF)-1\u03b1 and HIF-2\u03b1 orchestrate cellular responses to hypoxia and coordinate a transcriptional program that promote several aggressive features in CM, such as angiogenesis, epithelial-mesenchymal transition, metastasis formation, metabolic rewiring, and immune escape. BRAF<jats:sup>V600E<\/jats:sup>, which is the most frequent mutation observed in CM patients, usually increases HIF-\u03b1 signaling not only in hypoxia, but also in normoxic CM cells, enabling HIF-1\u03b1 and HIF-2\u03b1 to continuously activate downstream molecular pathways. In this review, we aim to provide a comprehensive overview of the intricate role and regulation of HIF-1\u03b1 and HIF-2\u03b1 in CM, with a brief focus on the complex interactions between HIF-\u03b1 subunits and non-coding RNAs. We also discuss HIF-\u03b1-mediated cellular responses in normoxia along with the mechanisms that allow HIF-\u03b1 subunits to maintain their stability under normal oxygen conditions. Finally, we resume available evidence on potential therapeutic approaches aimed at targeting HIF-1\u03b1 and\/or HIF-2\u03b1.<\/jats:p>","DOI":"10.1186\/s12964-025-02173-4","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T13:44:41Z","timestamp":1744206281000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Unraveling the role of hypoxia-inducible factors in cutaneous melanoma: from mechanisms to therapeutic opportunities"],"prefix":"10.1186","volume":"23","author":[{"given":"Arianna","family":"Bellazzo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Montico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Guerrieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Colizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Steffan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Polesel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Fratta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"2173_CR1","doi-asserted-by":"publisher","first-page":"1331355","DOI":"10.3389\/fonc.2024.1331355","volume":"14","author":"KJ Bigos","year":"2024","unstructured":"Bigos KJ, Quiles CG, Lunj S, Smith DJ, Krause M, Troost EG, et al. 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