{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:24:08Z","timestamp":1792589048238,"version":"4.5.0"},"reference-count":67,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Belzutifan is a hypoxia-inducible factor-2\u03b1 (HIF-2\u03b1) inhibitor that received FDA approval in 2021 for treating cancers resulting from von Hippel-Lindau (VHL) disease, including clear cell renal cell carcinoma (ccRCC), followed by approval in 2023 for sporadic ccRCC that has progressed through multiple lines of therapy. HIF-2\u03b1 is a promising drug target, as VHL is commonly inactivated in ccRCC, which results in HIF-2\u03b1-mediated signaling that is considered central to tumorigenesis. Belzutifan has demonstrated efficacy in clinical trials in the first-line and subsequent line settings, and in combination with tyrosine kinase inhibitors. Despite being overall well tolerated, belzutifan has a distinct safety profile because of its unique mechanism of action. Anemia was the most common adverse event observed in clinical trials and is considered an on-target effect. Hypoxia is also frequently observed and commonly results in dose reductions, treatment discontinuation, and supplemental oxygen use. This review summarizes the rates of hypoxia seen in clinical trials of belzutifan in ccRCC. As the cause of hypoxia is not well understood, this review also discusses possible mechanisms of hypoxia based on preclinical studies of the HIF pathway and HIF-2\u03b1 inhibitors. Finally, this review proposes monitoring and management recommendations for clinicians prescribing belzutifan to ccRCC patients.<\/jats:p>","DOI":"10.3390\/ijms26157094","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T11:52:47Z","timestamp":1753271567000},"page":"7094","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Belzutifan-Associated Hypoxia: A Review of the Novel Therapeutic, Proposed Mechanisms of Hypoxia, and Management Recommendations"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6929-5562","authenticated-orcid":false,"given":"John","family":"Kucharczyk","sequence":"first","affiliation":[{"name":"Department of Oncology and Hematology, Perlmutter Cancer Center at NYU Langone Hospital\u2014Long Island, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6858-4747","authenticated-orcid":false,"given":"Anshini","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minas","family":"Economides","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41585-019-0211-5","article-title":"The Cancer Genome Atlas of renal cell carcinoma: Findings and clinical implications","volume":"16","author":"Linehan","year":"2019","journal-title":"Nat. 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