Nucleotide Metabolism Reprogramming Drives Cardiovascular Inflammation in Obesity

Overview

Obesity induces inhibitory phosphorylation of SAMHD1 in macrophages, leading to cytosolic dNTP accumulation, mitochondrial DNA synthesis and oxidation, and hyperactivation of the NLRP3 inflammasome. This SAMHD1–dNTP–mtDNA–NLRP3 axis links nutrient excess to sustained cardiovascular inflammation, contributing to atherosclerosis, obesity cardiomyopathy, and ischemia–reperfusion injury.

Background

Obesity is a major modifiable risk factor for cardiovascular disease, primarily through chronic low-grade inflammation that promotes endothelial dysfunction and accelerates atherosclerosis. The NLRP3 inflammasome is a key mediator of sterile inflammation in cardiovascular pathology, activated by metabolic stressors enriched in obesity such as cholesterol crystals and saturated fatty acids. However, the molecular convergence linking nutrient excess to sustained NLRP3 activation was previously unclear. Recent evidence identifies nucleotide metabolism reprogramming, specifically SAMHD1 phosphorylation and dNTP accumulation, as a novel upstream checkpoint in macrophage inflammatory activation.

Data Highlights

Key mechanistic insights include: obesity-induced inhibitory phosphorylation of SAMHD1 leads to cytosolic dNTP accumulation; excess dNTPs are transported into mitochondria via SLC25 transporters; this drives uncontrolled mitochondrial DNA synthesis and oxidative damage; resulting in hyperactivation of the NLRP3 inflammasome. These findings were conserved across human, mouse, and zebrafish macrophage models and linked to major cardiovascular pathologies associated with obesity.

Key Findings

• Obesity promotes inhibitory phosphorylation of SAMHD1, impairing its dNTP hydrolase activity.
• Accumulated cytosolic dNTPs are imported into mitochondria through SLC25 transporters, causing excessive mtDNA synthesis and oxidative damage.
• mtDNA oxidation triggers hyperactivation of the NLRP3 inflammasome, driving IL-1β and IL-18 production.
• This SAMHD1–dNTP–mtDNA–NLRP3 axis serves as a unifying upstream checkpoint linking diverse metabolic stressors to macrophage inflammation.
• Therapeutic targets include selective SLC25 inhibition, modulation of kinases preserving SAMHD1 function, and mitochondria-targeted antioxidants.
• This metabolic checkpoint contributes to accelerated atherosclerosis, diastolic dysfunction in obesity cardiomyopathy, and worsened ischemia–reperfusion injury.

Clinical Implications

Understanding the SAMHD1–dNTP–mtDNA–NLRP3 axis offers novel therapeutic opportunities to target the metabolic initiation phase of obesity-driven cardiovascular inflammation. Interventions aimed at preserving SAMHD1 activity, inhibiting mitochondrial nucleotide transport, or reducing mitochondrial oxidative stress may prevent or mitigate inflammation-mediated cardiovascular damage. This precision approach could complement existing therapies by addressing the root metabolic cause rather than downstream inflammatory effects.

Conclusion

Reprogramming of nucleotide metabolism represents a critical upstream mechanism linking obesity to sustained cardiovascular inflammation via macrophage NLRP3 inflammasome activation. Targeting this pathway may enable novel precision therapies to reduce obesity-associated cardiovascular risk.

References

1. Liu, Zhong et al. 2023 -- Obesity-induced SAMHD1 phosphorylation drives nucleotide metabolism reprogramming and NLRP3 inflammasome activation