Identification of HIF1A as a therapeutic target during SARS-CoV-2–associated lung injury
Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We, therefore, tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF stabilizer vadadustat. Subsequent studies in genetic models implicated alveolus-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase II trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n = 448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the 2 groups. Vadadustat treatment induced surrogate HIF target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline fraction of inspired oxygen of 80% or higher (n = 106), the estimated probability of the primary outcome was 12.1% (vadadustat) versus 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2-associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.
Authors
- Holger K. Eltzschig (ORCID: https://orcid.org/0000-0002-5676-6473)
- Xiaoyi Yuan (ORCID: https://orcid.org/0000-0002-2898-6495)
- Yafen Liang (ORCID: https://orcid.org/0000-0001-7902-7836)
- Paulina Sergot (ORCID: https://orcid.org/0000-0003-0796-8009)
- Samuel Luber (ORCID: https://orcid.org/0000-0002-5074-6543)
- Katherine Figarella (ORCID: https://orcid.org/0000-0003-3305-9167)
- Constanza de Dios (ORCID: https://orcid.org/0000-0003-0230-5222)
- Alparslan Turan (ORCID: https://orcid.org/0000-0001-9862-9306)
- Steven K. Burke (ORCID: https://orcid.org/0000-0002-9073-0239)
- Adit A. Ginde (ORCID: https://orcid.org/0000-0003-2325-206X)
- Daniel I. Sessler (ORCID: https://orcid.org/0000-0001-9932-3077)
- Charles Green (ORCID: https://orcid.org/0000-0003-2973-4625)
- Hongfang Liu (ORCID: https://orcid.org/0000-0003-2529-7341)
- David Robinson (ORCID: https://orcid.org/0000-0002-0729-5011)
- Robert Suchting (ORCID: https://orcid.org/0000-0002-2822-3754)
- In Hyuk Bang (ORCID: https://orcid.org/0000-0003-4666-7655)
- Bentley J. Bobrow
- Marie–Françoise Doursout (ORCID: https://orcid.org/0000-0002-5684-3483)
- Paul Potnuru (ORCID: https://orcid.org/0000-0003-4359-5342)
- Ji-Eun Kim (ORCID: https://orcid.org/0000-0003-0092-2147)
- Yanyu Wang (ORCID: https://orcid.org/0000-0001-5731-3225)
- Tingting Mills (ORCID: https://orcid.org/0000-0002-6041-4788)
- George W. Williams (ORCID: https://orcid.org/0000-0001-9079-610X)
Institutions
- McGovern Institute for Brain Research (US)
- Akebia Therapeutics (United States) (US)
- Houston Institute for Clinical Research (US)
- The University of Texas Health Science Center (US)
- Artificial Intelligence in Medicine (Canada) (CA)
- Pain and Rehabilitation Medicine (US)
- The University of Texas Health Science Center at Houston (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1172/jci.insight.191463
- Citations
- 3
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- U.S. Department of Defense
- Akebia Therapeutics
- National Institute of Allergy and Infectious Diseases