NAD+ metabolism-based immunoregulation and therapeutic potential

The dynamics of NAD^+ homeostasis is characterized by a balance of synthesis, consumption and regeneration. The role of NAD^+ in immunomodulation is context and signaling pathway specific. The manipulation of NAD^+ bioavailability represents a promising therapeutic strategy for inflammatory diseases. Nicotinamide adenine dinucleotide (NAD^+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD^+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD^+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD^+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD^+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD^+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.

• Publication year

  2023

• Venue

  Cell & Bioscience

• Publication date

  2023-05-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s13578-023-01031-5PMID 37165408PMCID 10171153
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Evolving concepts in NAD+ metabolism.

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  2020cited by this paper
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  2020cited by this paper
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  2020cited by this paper
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  2020influential reference
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  2020cited by this paper
• Inflammation in Heart Failure: JACC State-of-the-Art Review.

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  2020cited by this paper
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