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HC often involves parathyroid hormone\u2013related protein (PTHrP), and the role of hypoxia-inducible factor 2 (HIF-2) is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell\u2013autonomous inflammatory\/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP, and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2\u2013dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including the EPO locus in a TG with paraneoplastic polycythemia). As in TGs, paraneoplastic HC in patients was associated with clear-cell (cc)RCC (and sarcomatoid\/rhabdoid differentiation) and was rapidly corrected by PT2977\/belzutifan, which unlike bisphosphonates downregulated PTHrP. Our data support evaluating HIF-2 antagonists for ccRCC patients with paraneoplastic HC, which may serve as a predictive biomarker.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This study uncovers a direct role for HIF-2 in driving humoral HC of malignancy in ccRCC through transcriptional activation of PTHLH (encoding PTHrP), identifies HC (and PTHrP) as potentially predictive biomarkers of HIF-2 engagement, and sets a foundation for the evaluation of HIF-2 antagonists for HC management in patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0638","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T14:01:32Z","timestamp":1760018492000},"page":"2485-2504","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["HIF-2\u2013Dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear-Cell Renal Cell Carcinoma"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3960-2805","authenticated-orcid":false,"given":"Arijit","family":"Mal","sequence":"first","affiliation":[{"name":"1Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9246-9321","authenticated-orcid":false,"given":"Bingqing","family":"Xie","sequence":"additional","affiliation":[{"name":"1Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Hematology-Oncology Division, Department of Internal Medicine, University of Texas 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