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Life sciences · Journal article
Journal of Physiology and Biochemistry · September 26, 2026
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Obesity has become a serious global public health challenge, characterized by chronic, sterile, low-grade inflammation with excessive NLRP3 inflammasome activation; however, the mechanism underlying the reduced activation threshold remains unclear. A recent study by Liu et al. demonstrated that obesity induces the phosphorylation and inactivation of SAMHD1, leading to a massive accumulation of cytosolic dNTPs. This causes excess dNTPs to enter mitochondria via the PNC1/2 transporters, bypassing the classical CMPK2 salvage synthesis pathway and triggering uncontrolled mtDNA synthesis and oxidative damage, ultimately resulting in the excessive activation of NLRP3 and an inflammatory response. Based on this finding, this paper presents a “double-edged sword” model of nucleotide metabolic reprogramming in obesity-related inflammation. Early reversible inactivation of SAMHD1 may represent a metabolic adaptive response that confers functional benefits to macrophages; however, once metabolic stress persists and causes nucleotide metabolic reprogramming to exceed a yet-to-be-defined threshold, an inflammatory positive feedback loop may be established. In terms of clinical translation, targeting PNC1/2 could specifically inhibit NLRP3 activation, which may provide new upstream intervention strategies for various aseptic inflammatory conditions such as gout; however, this approach also carries potential risks of mitochondrial toxicity and impaired anti-infective immunity. Future efforts should focus on macrophage-specific delivery, precision interventions tailored to disease stages, and precise anti-inflammatory strategies based on biomarkers such as circulating dNTPs, p-SAMHD1, and ox-mtDNA, thereby advancing the clinical translation of metabolism-related inflammation within safe parameters.