ArticleSignal transduction and targeted therapy2023
Hypoxia-inducible factor upregulation by roxadustat attenuates drug reward by altering brain iron homoeostasis.
Article in Signal transduction and targeted therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 11 citations in OpenAlex.
- Decoding the Neural Circuit Underlying Context-Cue Association in Retrieval of Morphine Reward Memory.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.Nature neuroscience · 2026Article
- HIF1 Stabilization by Roxadustat Improves Cognition and Prevents Neuron Loss in Alzheimer's Diseases In Vivo.Biology · 2026Article
- Clinically approved HIF-PHIs modulate redox metabolism, cell growth, and angiogenesis independent of HIF-1α/HIF-2α.Redox biology · 2026Article
- High‑altitude polycythemia: Unveiling the molecular landscape beyond erythropoietin (Review).International journal of molecular medicine · 2026Review
- Bidirectional genetic and phenotypic links between smoking and striatal iron content involving dopaminergic and inflammatory pathways.Addiction (Abingdon, England) · 2026Article
- Article
- Brain-wide mapping of acute hypoxia-induced neuronal activation in mice: A c-Fos immunofluorescence study.IBRO neuroscience reports · 2025Article
- Role of RET-Regulated GDNF-GFRα1 Endocytosis in Methamphetamine-Induced Neurotoxicity.International journal of molecular sciences · 2025Article
- Drug delivery pathways to the central nervous system via the brain glymphatic system circumventing the blood-brain barrier.Exploration (Beijing, China) · 2025Review
- Proteome-wide Mendelian randomization and functional studies uncover therapeutic targets for polycystic ovarian syndrome.American journal of human genetics · 2024Article
- Mouse embryonic kidney transplantation identifies maturation defects in the medulla.Scientific reports · 2024Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Substance use disorder remains a major challenge, with an enduring need to identify and evaluate new, translational targets for effective treatment. Here, we report the upregulation of Hypoxia-inducible factor-1α (HIF-1α) expression by roxadustat (Rox), a drug developed for renal anemia that inhibits HIF prolyl hydroxylase to prevent degradation of HIF-1α, administered either systemically or locally into selected brain regions, suppressed morphine (Mor)-induced conditioned place preference (CPP). A similar effect was observed with methamphetamine (METH). Moreover, Rox also inhibited the expression of both established and reinstated Mor-CPP and promoted the extinction of Mor-CPP. Additionally, the elevation of HIF-1α enhanced hepcidin/ferroportin 1 (FPN1)-mediated iron efflux and resulted in cellular iron deficiency, which led to the functional accumulation of the dopamine transporter (DAT) in plasma membranes due to iron deficiency-impaired ubiquitin degradation. Notably, iron-deficient mice generated via a low iron diet mimicked the effect of Rox on the prevention of Mor- or METH-CPP formation, without affecting other types of memory. These data reveal a novel mechanism for HIF-1α and iron involvement in substance use disorder, which may represent a potential novel therapeutic strategy for the treatment of drug abuse. The findings also repurpose Rox by suggesting a potential new indication for the treatment of substance use disorder.
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