Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming

TLDR

Nrf2 is a key regulator of inflammation, yet its influence on cytosolic nucleic‑acid sensing remains unclear. The authors propose that pharmacologic Nrf2 activation could serve as a therapeutic strategy for STING‑dependent inflammatory diseases. Nrf2 down‑regulates STING by destabilizing STING mRNA, thereby reducing its expression. This repression of STING—enhancing DNA‑virus susceptibility—can be triggered by metabolic reprogramming or Nrf2 activators such as 4‑octyl‑itaconate and sulforaphane, and it also dampens type I IFN production in patients with STING‑dependent interferonopathies.

Abstract

The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases.