Summary: New research from Johns Hopkins Medicine identifies biliverdin reductase A (BVRA) as a critical protector of neurons against oxidative stress. The enzyme performs this protective role independently of its well-known enzymatic function of producing bilirubin. Using genetically engineered mice and a combination of biochemical and genomic analyses, the team shows BVRA binds directly to NRF2, a master transcriptional regulator of antioxidant defenses, to activate genes that preserve neuronal health.
Crucially, BVRA’s protection of brain cells does not require bilirubin production: BVRA mutants unable to synthesize bilirubin still supported NRF2 activity and maintained neuronal resilience. These findings reveal a noncanonical BVRA–NRF2 axis with implications for aging, cognitive function, and neurodegenerative diseases such as Alzheimer’s disease.
Key Points
- Direct NRF2 Regulation: BVRA physically interacts with NRF2 to control antioxidant and cytoprotective gene programs, separate from its role in bilirubin synthesis.
- Relevance to Neurodegeneration: Loss of BVRA disrupted NRF2 signaling and reduced expression of antioxidant genes, a pattern observed in neurodegenerative conditions including Alzheimer’s disease.
- Therapeutic Opportunity: Targeting BVRA’s nonenzymatic function could strengthen neuronal defenses against oxidative damage and offer a new strategy for treating neurodegenerative disorders.
The study, supported by the National Institutes of Health and published in Proceedings of the National Academy of Sciences, was led by Bindu Paul, M.S., Ph.D., associate professor at the Johns Hopkins University School of Medicine. The research used genetic knockout models, transcriptomics, chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing, and biochemical binding assays to define the relationship between BVRA and NRF2 in the brain.
Initial experiments showed that mice lacking both BVRA and NRF2 genes did not survive, suggesting a vital interaction between the two proteins. Mice deficient in BVRA alone exhibited impaired NRF2 function and lower expression of NRF2 target genes, including those that generate antioxidants and support mitochondrial function. In cultured cells and brain tissue, BVRA and NRF2 were shown to bind directly and co-regulate gene networks responsible for oxygen transport, immune signaling, and mitochondrial health—pathways central to neuronal survival under oxidative stress.
To test whether BVRA’s protective role depended on bilirubin generation, researchers created BVRA mutants that were enzymatically inactive for bilirubin production. These mutants retained the ability to bind NRF2 and sustain antioxidant gene expression, confirming that BVRA’s neuroprotective activity can be independent of its catalytic function. This nonenzymatic role positions BVRA as an integrator of both lipophilic and hydrophilic antioxidant systems in the brain.
First author Chirag Vasavda, M.D., Ph.D., emphasized that BVRA’s functions extend beyond bilirubin synthesis to become a molecular integrator of cellular defense mechanisms. Co-first author Ruchita Kothari highlighted how mechanistic discovery over time led to this insight. Co-corresponding author Solomon H. Snyder, M.D., noted the therapeutic promise of targeting the BVRA–NRF2 axis to slow or prevent neurodegenerative decline.
The team plans follow-up studies to examine how BVRA–NRF2 signaling is altered in established mouse models of Alzheimer’s disease and to assess whether modifying BVRA activity can alter disease progression. The researchers describe this work as a product of a sustained, multidisciplinary collaboration spanning neuroscience, biochemistry, genomics, and clinical investigation.
Funding and contributions: Support came from a range of sources including the American Heart Association, the Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment, multiple NIH grants, the Department of Defense, Department of Veterans Affairs, and several private foundations and donors. The project team included investigators from Johns Hopkins and collaborating institutions, reflecting a broad, multi-institutional effort.
About this neuroscience research news
Author: Alexandria Carolan
Source: JHU
Contact: Alexandria Carolan – JHU
Image: The image is credited to Neuroscience News
Original Research: Open access. “Biliverdin reductase A is a major determinant of protective NRF2 signaling” by Bindu Paul et al., PNAS.
Abstract
Biliverdin reductase A is a major determinant of protective NRF2 signaling
Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism that generates the lipophilic antioxidant bilirubin, also exerts a critical nonenzymatic role in redox regulation. Using phylogenetic, genetic, biochemical, and enzymatic approaches, the study demonstrates BVRA’s nonenzymatic antioxidant activity and reveals a physical and genetic interaction with nuclear factor erythroid-derived factor-like 2 (NRF2), a key transcriptional regulator of cellular redox signaling.
ChIP-seq and RNA-seq analyses show that BVRA and NRF2 coordinate expression of antioxidant genes, many of which are dysregulated in neurodegenerative conditions such as Alzheimer’s disease. This noncanonical BVRA–NRF2 axis controls an essential redox pathway in neuroprotection and positions BVRA as a dual-function integrator of antioxidant defense across both lipophilic and hydrophilic compartments in the brain.