Duncan NRI Faculty and Staff Publications
Language
English
Publication Date
10-7-2025
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2513120122
PMID
41026820
Abstract
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.
Keywords
NF-E2-Related Factor 2, Oxidoreductases Acting on CH-CH Group Donors, Signal Transduction, Animals, Humans, Mice, Oxidation-Reduction, Antioxidants, Brain, HEK293 Cells, NRF2 signaling, biliverdin reductase A, gene regulation, neuroprotection, oxidative stress
Published Open-Access
yes
Recommended Citation
Vasavda, Chirag; Kothari, Ruchita; Ammal Kaidery, Navneet; et al., "Biliverdin Reductase A Is a Major Determinant of Protective NRF2 Signaling" (2025). Duncan NRI Faculty and Staff Publications. 149.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/149
Included in
Genetic Phenomena Commons, Medical Genetics Commons, Neurology Commons, Neurosciences Commons