Molecular Pathways in Adipose Inflammation: New Insights into Cardiometabolic Risk

SAMHD1 phosphorylation links adipose mitochondrial DNA accumulation to NLRP3 inflammasome activation, driving adipose inflammation in obesity and potentially contributing to systemic metabolic dysregulation.

Phosphorylation of SAMHD1 reduces its nuclease activity in adipocytes, allowing mitochondrial DNA to accumulate and trigger the NLRP3 inflammasome. That activation amplifies caspase-1–dependent signaling, increasing IL-1β and IL-18 release and recruiting macrophages into adipose tissue. Results from preclinical and translational models point to a tissue‑intrinsic inflammatory driver that may worsen metabolic control.

Therapeutic strategies under consideration include small molecules or biologics that block the NLRP3 inflammasome to prevent mtDNA-driven inflammation. Other approaches highlighted are agents that preserve SAMHD1 nuclease function, kinase modulators that prevent its phosphorylation, and interventions that limit mitochondrial stress and mtDNA release to reduce adipose‑driven inflammation.

Preclinical and translational readouts to support clinical development would include reduced adipose inflammation, improved insulin sensitivity, and lower atherogenic markers. The primary target populations are patients with obesity, metabolic syndrome, nonalcoholic fatty liver disease, and elevated cardiovascular risk.

For specialists in endocrinology, hepatology, cardiology, lipidology, and obesity medicine, these data reframe adipose inflammation as a potentially modifiable target—one that warrants target‑engagement studies to establish safety and mechanism in humans.

Key Takeaways:

• Identification of SAMHD1 phosphorylation as a driver of adipose inflammation points to an upstream therapeutic target for reducing obesity‑related metabolic inflammation.
• Evidence to date is preclinical and translational; clinical efficacy and safety of SAMHD1‑ or NLRP3‑targeted interventions remain to be established in humans.
• Emerging trials targeting mtDNA‑driven inflammation may influence risk stratification for patients with obesity and metabolic disease; clinicians and trialists should watch for mechanistic safety and target‑engagement data.