CD38 functions mainly as a multifunctional ectoenzyme, controlling the metabolism of nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular energy metabolism and signaling. In cancers like multiple myeloma, CD38 has been targeted effectively using monoclonal antibodies such as daratumumab and isatuximab, which block its activity, inhibiting tumor growth and promoting cell death. This clinical success has laid the foundation for expanding CD38-targeted therapies into the realms of cardiovascular and cerebrovascular care, where dysregulated NAD+ metabolism and inflammation are underlying factors.

Intriguingly, multiple myeloma patients often present with coexisting cardiovascular complications, including heart failure, arrhythmias, and thrombotic disorders, largely due to the systemic burden of the disease and factors like amyloidosis and renal dysfunction. These overlapping pathologies underscore the heart-brain interplay mediated by CD38. Research has demonstrated that targeting CD38 can alleviate cardiac dysfunction triggered by amyloid deposits, suggesting a dual benefit: combatting cancer progression while potentially preserving cardiac function.

Neurodegenerative and neuroinflammatory conditions also share pathological hallmarks linked to aberrant NAD+ metabolism and oxidative stress, where CD38’s role as a NADase enzyme becomes detrimental. This has sparked scientific interest in leveraging CD38 inhibitors to modulate brain inflammation and prevent neuronal loss. Early investigations reveal that compounds capable of inhibiting CD38 can suppress glial activation and reduce cytokine production, pathways crucial in neurodegenerative disease progression, suggesting a new frontier in neuroprotection.

Beyond antibodies, the search for effective CD38 inhibitors has expanded into several chemical classes, each with distinct mechanisms and therapeutic prospects. One such class is the NAD+ analogs, synthetic molecules designed to inhibit the NADase activity of CD38 directly, thus preserving intracellular NAD+ levels. Although still in preclinical stages with limited data on their cardiovascular and neurological effects, these analogs represent a promising avenue for modulating metabolic dysfunction in disease states.

Natural compounds have also emerged as potential CD38 inhibitors. Flavonoids—plant-derived antioxidants found abundantly in fruits and vegetables—exhibit notable inhibitory activity against CD38. Luteolin, apigenin, and quercetin have been shown to bolster myocardial and endothelial function by maintaining NAD+ availability, thereby protecting cardiac tissue against ischemia-reperfusion injury. Moreover, certain flavonoids dampen neuroinflammatory responses, providing a natural route to support brain health through CD38 modulation.

A groundbreaking breakthrough in this field is the identification of thiazoloquin(az)olin(on)e compounds, particularly one known as 78c. This novel chemical entity acts as a potent and selective inhibitor of CD38 and has demonstrated remarkable cardioprotective effects in preclinical experiments. Animal models subjected to ischemic heart injury exhibited significant improvement in myocardial contractility, decreased infarct size, and enhanced coronary perfusion following treatment with 78c, highlighting its therapeutic potential in acute cardiac events.

In the central nervous system, 78c has shown efficacy in mitigating saturation fat-induced neuroinflammation by raising NAD+ levels in astrocyte cultures. This highlights an intriguing link between metabolic stress, inflammation, and CD38 activity in the brain, positioning 78c and related compounds as candidates for novel treatments against neurodegenerative diseases involving chronic inflammation.

Despite these promising developments, the molecular mechanisms governing CD38’s dual role in cardiac and cerebral tissues require deeper elucidation. Future research endeavors aim to unravel its complex signaling networks and interactions with other cellular pathways, which may reveal new targets for intervention. Such insights will be crucial for designing inhibitors that maximize therapeutic benefits while minimizing adverse effects.

The integration of advanced technologies such as immunotherapy and gene editing offers exciting possibilities for enhancing CD38-targeted treatments. For instance, combining monoclonal antibodies with immune checkpoint inhibitors or CRISPR-mediated gene modulation could refine therapeutic efficacy and provide personalized approaches to treating cardiovascular and neurological diseases linked to CD38 dysregulation.

Moreover, the clinical translation of CD38 inhibitors from oncology to cardiology and neurology presents logistical and regulatory challenges. Rigorous clinical trials are needed to assess safety profiles, dosing regimens, and long-term outcomes in populations afflicted with heart and brain conditions. Collaborative efforts across disciplines will be essential to accelerate these investigations and validate CD38 inhibitors as versatile therapeutics.

The prospect of applying CD38-targeted therapies represents a holistic vision for medicine where interconnected systems—such as the heart and brain—are treated in an integrated manner. This approach not only addresses symptomatic manifestations but also targets fundamental molecular drivers of disease, raising hope for more effective interventions against some of the most debilitating illnesses worldwide.

In summary, CD38 stands at a promising intersection between oncology, cardiology, and neurology. The expanding repertoire of inhibitors—from monoclonal antibodies to small molecule compounds and natural products—provides a multifaceted toolkit for safeguarding heart and brain health. As research continues to unveil CD38’s diverse biological functions and therapeutic possibilities, it may revolutionize the way we confront cardiovascular and cerebrovascular diseases, offering renewed hope for millions of patients globally.

Subject of Research: The role of CD38 enzyme and its inhibitors in treating cardiovascular and cerebrovascular diseases, expanding from its established use in hematologic malignancies.

Article Title: CD38 connects the heart and brain.

Article References:
Tao, Y., Duan, J., Huang, K. et al. CD38 connects the heart and brain. Transl Psychiatry 15, 342 (2025). https://doi.org/10.1038/s41398-025-03597-9

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41398-025-03597-9

Werner syndrome manifests clinically with characteristics typically observed in elderly individuals, including cataracts, osteoporosis, hair thinning, and cardiovascular disease, but with an onset as early as the third decade of life. The WRN gene, which encodes a helicase involved in DNA repair and genome maintenance, plays a protective role in cellular longevity. Its loss of function leads to accelerated cellular senescence and genomic instability. However, the exact mechanisms by which WRN deficiency drives premature aging at the mitochondrial and metabolic level have remained elusive—until now.

This new study reveals that cells lacking functional WRN protein suffer from a significant depletion of mitochondrial nicotinamide adenine dinucleotide (NAD+), a vital coenzyme central to energy metabolism, redox reactions, and mitochondrial health. NAD+ serves as a substrate for key enzymes involved in DNA repair, gene expression regulation, and metabolic adaptation. Deficiencies in mitochondrial NAD+ compromise oxidative phosphorylation, leading to reduced ATP production and enhanced mitochondrial dysfunction, which accelerates cellular aging features observed in WS.

Through comprehensive gene-set enrichment analyses and transcriptomic profiling, the researchers identified that WRN-deficient mesenchymal stem cells (MSCs) exhibit widespread disruptions in metabolic and mitochondrial pathways. Notably, pathways governing NAD+ biosynthesis and salvage were significantly downregulated, suggesting that WRN plays a crucial role in maintaining intracellular NAD+ homeostasis. Intriguingly, treatment with nicotinamide riboside (NR), a precursor molecule that elevates cellular NAD+ levels, robustly rescued many of these metabolic defects within just 24 hours.

NR supplementation not only restored the expression of genes involved in mitochondrial function and proliferation but also mitigated cellular senescence markers in WS-derived MSCs and primary fibroblasts. Senescence-associated β-galactosidase (SA-β-Gal) staining, a gold-standard assay for detecting aging cells, showed a marked decrease in NR-treated WRN-deficient cells, confirming the rejuvenating effect of NAD+ augmentation. Additional assays demonstrated improved nuclear retention of HMGB1, a chromatin-associated protein whose cytoplasmic translocation is a hallmark of senescent cells, further corroborating the anti-senescence potential of NR.

Despite these promising results, the study carefully notes that NAD+ replenishment, while beneficial, did not completely reverse all dysfunctions in WRN-deficient cells. This finding underscores the multifaceted role of the WRN helicase, whose DNA repair and genome stability functions cannot be fully substituted by metabolic intervention alone. Nonetheless, the capacity of NR to partially restore cellular health highlights NAD+ metabolism as a viable therapeutic axis that could be exploited in mitigating premature aging syndromes.

Mechanistically, the interplay between WRN and NAD+ metabolism appears complex, involving coordinated regulation of genes that drive NAD+ biosynthetic pathways. Loss of WRN disrupts this balance, precipitating mitochondrial malfunctions and bioenergetic collapse that accelerate cellular aging. The findings also raise compelling questions about how subcellular NAD+ pools are regulated and distributed, and how these dynamics intersect with DNA repair and longevity pathways.

This work aligns with a growing body of research emphasizing the centrality of NAD+ homeostasis in aging and age-associated diseases such as neurodegeneration, metabolic disorders, and cancer. The ability to pharmacologically modulate NAD+ levels through precursors like NR or nicotinamide mononucleotide (NMN) has sparked considerable interest in developing novel anti-aging therapeutics. The present study strengthens this paradigm by providing concrete evidence that NAD+ augmentation can dampen senescence in the context of a defined genetic premature aging disorder.

Future investigations will be critical in unraveling the precise molecular crosstalk between WRN function, mitochondrial integrity, and NAD+ metabolism. Moreover, studies extending beyond in vitro models into animal systems and clinical settings will be invaluable to evaluate the translational potential of NAD+ boosting compounds for WS patients. If successful, such interventions could herald a new class of therapeutics aimed at mitigating cellular aging and extending healthspan in diverse human populations.

The implications of these discoveries extend far beyond Werner syndrome, offering valuable insight into the universal biological processes that regulate aging and cell vitality. By linking mitochondrial NAD+ depletion to proliferative defects and senescence, this research paves the way for targeted metabolic therapies that may one day combat the fundamental drivers of human aging.

In conclusion, Lautrup, Fang, and colleagues have provided compelling biological evidence that diminished mitochondrial NAD+ is a key contributor to premature cellular aging in WRN-deficient cells. Their work illuminates important pathways susceptible to intervention and offers hope for effective treatments that address the metabolic foundations of premature aging. This landmark study propels the field closer to harnessing metabolic modulation as a legitimate strategy in the fight against age-related decline and genetic aging disorders.

Subject of Research: Cells
Article Title: Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation
News Publication Date: April 2, 2025
Web References: http://dx.doi.org/10.18632/aging.206236
Image Credits: Copyright © 2025 Lautrup et al., distributed under the Creative Commons Attribution License (CC BY 4.0)
Keywords: aging, Werner syndrome, premature aging, NAD+, mitochondria, proliferation