Figure 8. Mechanistic link from NQO1 activation, de-novo NAD⁺ synthesis to SIRT1-FOXO1 signaling.

NQO1 activation induces rapid downregulation of LAT1, resulting in decreased de-novo NAD⁺ synthesis, together with PARP-1 hyperactivation to induce a rapid depletion of intracellular NAD⁺. Because SIRT1 relies on NAD⁺ for the deacetylation reaction, the reduced NAD⁺ results in the repression of SIRT1 activity, leading to the increased accumulation of acetylated FOXO1 which translocates to the nuclear to transcriptionally activate apoptotic signaling.