Biliverdin reductase A is a major determinant of protective NRF2 signaling
Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer's disease. Thus, this noncanonical BVRA-NRF2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings position BVRA as a dual-function integrator of antioxidant defense across both lipophilic and hydrophilic compartments, bridging these two distinct modes of redox protection in the brain.
Authors
- Bindu D. Paul (ORCID: https://orcid.org/0000-0002-1862-6103)
- Chirag Vasavda (ORCID: https://orcid.org/0000-0003-4558-4698)
- Priyanka Kothari (ORCID: https://orcid.org/0000-0002-1791-5093)
- Cristina Ricco (ORCID: https://orcid.org/0000-0002-8103-627X)
- Bobby Thomas (ORCID: https://orcid.org/0000-0001-9244-9726)
- Solomon H. Snyder (ORCID: https://orcid.org/0000-0002-6818-7022)
- Eugenio Barone (ORCID: https://orcid.org/0000-0002-7028-4251)
- L. Aravind (ORCID: https://orcid.org/0000-0003-0771-253X)
- Kalyani Chaubey (ORCID: https://orcid.org/0000-0002-6378-6739)
- Ruchita Kothari (ORCID: https://orcid.org/0000-0002-9575-6200)
- Michael C. Ostrowski (ORCID: https://orcid.org/0000-0003-2948-6297)
- Navneet Ammal Kaidery (ORCID: https://orcid.org/0000-0002-3226-2107)
- Lakshminarayan M. Iyer (ORCID: https://orcid.org/0000-0002-4844-2022)
- Sudarshana M. Sharma (ORCID: https://orcid.org/0000-0002-9745-0061)
- Ryan S. Dhindsa (ORCID: https://orcid.org/0000-0002-8965-0813)
- Sunil Jamuna Tripathi (ORCID: https://orcid.org/0000-0001-9107-2437)
- Julia E. Lefler
- Samaneh Saberi (ORCID: https://orcid.org/0000-0002-5246-9092)
- Andrew A. Pieper (ORCID: https://orcid.org/0000-0001-6299-6577)
- Adele M. Snowman
- Suwarna Chakraborty (ORCID: https://orcid.org/0000-0001-9456-4322)
- Shruthi Shanmukha (ORCID: https://orcid.org/0000-0001-5659-2250)
Institutions
- Johns Hopkins University (US)
- Medical University of South Carolina (US)
- Baylor College of Medicine (US)
- University Hospitals of Cleveland (US)
- Discovery Institute (US)
- Johns Hopkins Medicine (US)
- Discovery Centre (CA)
- United States National Library of Medicine (US)
- MUSC Hollings Cancer Center (US)
- University Hospitals Cleveland Medical Center (US)
- Geriatric Research Education and Clinical Center (US)
- Louis Stokes Cleveland VA Medical Center (US)
- Neurological Research Institute (US)
- Drug Discovery Laboratory (Norway) (NO)
- Lieber Institute for Brain Development (US)
- University School (US)
- Case Western Reserve University (US)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-09-30
- DOI
- https://doi.org/10.1073/pnas.2513120122
- Citations
- 4
- Primary Topic
- Heme Oxygenase-1 and Carbon Monoxide
- Type
- article
- Field-Weighted Citation Impact
- 3.22