Sirtuin 1–Nuclear factor kappa B–Tissue Factor axis (SIRT1–NF-κB–TF axis)

The Sirtuin 1–Nuclear factor kappa B–Tissue Factor (SIRT1–NF-κB–TF) axis is a critical regulatory pathway that integrates cellular metabolism with the control of inflammation and coagulation, a process known as thromboinflammation (Zhang et al., 2009; Rothgiesser et al., 2010). Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that serves as a metabolic sensor and a potent inhibitor of the pro-inflammatory transcription factor Nuclear factor kappa B (NF-κB). By deacetylating the p65 (RelA) subunit of NF-κB at the Lys310 residue, SIRT1 suppresses its transcriptional activity, thereby preventing the induction of Tissue Factor (TF), the primary initiator of the extrinsic coagulation cascade (Yeung et al., 2004; Stein et al., 2010). Dysregulation of this axis, often characterized by reduced SIRT1 activity and elevated NF-κB/TF expression, is a hallmark of various pathological states including atherosclerosis, sepsis, and severe viral infections such as COVID-19, where it drives excessive clotting and systemic inflammation. Therapeutic strategies targeting this axis focus on SIRT1-activating compounds (STACs) or NAD+ precursors to restore the inhibitory control over NF-κB and TF, offering a dual-action approach to treat both the inflammatory and thrombotic components of disease. This axis represents a significant therapeutic target for mitigating vascular damage and improving outcomes in patients with chronic metabolic and acute inflammatory conditions.

Other names

SIRT1-NF-kB-TF axisSIRT1-NF-kappaB-Tissue Factor axisThromboinflammatory SIRT1-NF-kB-TF axisSIRT1-mediated regulation of Tissue Factor

SIRT1 acts as an NAD+-dependent deacetylase that targets the p65 (RelA) subunit of the NF-κB complex, specifically deacetylating it at the Lys310 residue. This modification inhibits the transcriptional activity of NF-κB, thereby preventing the upregulation of Tissue Factor (TF) and other pro-inflammatory genes, which collectively reduces the thromboinflammatory response.