Glucose Metabolism Mediates Feedback Control of Innate Immune Signaling in Human Macrophages

<jats:p>Glucose metabolism is pivotal in regulating innate immune responses in primary human monocyte-derived macrophages (MDMs). Lipopolysaccharide (LPS) stimulation induces both inflammatory and antiviral programs; however, despite the established importance of glucose metabolism in these responses, its precise role in coordinating them remains poorly defined. Here, we identify the STAT1/NF-κB/IRF5 signaling axis as a key mediator linking glucose metabolism to inflammatory responses through the upregulation of the rate-limiting glycolytic enzyme PFKFB3. We found that LPS triggered delayed expression and activation of NF-κB p65, accompanied by increased expression of inflammatory target genes, including CD38 and CD40. Using complementary pharmacological and genetic approaches, we demonstrate that glycolysis and PFKFB3 activity are required for NF-κB p65 expression and activation. Strikingly, inhibition of PFKFB3 also suppressed LPS-induced STAT1 activation and nuclear translocation, revealing a glucose-dependent amplification loop that potentiates STAT1-mediated antiviral and NF-κB p65-mediated inflammatory responses. Collectively, these findings establish a mechanistic link between glycolytic metabolism and STAT1/IRF5- and NF-κB-dependent transcriptional programs in human MDMs responding to LPS, highlighting potential therapeutic targets for modulating innate immune responses in inflammatory disease.</jats:p>