The cGAS-STING pathway as a therapeutic target in inflammatory diseases

Nat Rev Immunol. 2021 Sep;21(9):548-569. doi: 10.1038/s41577-021-00524-z. Epub 2021 Apr 8.

Abstract

The cGAS-STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage. Underlying this broad involvement of the cGAS-STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules. Insights into the structural and molecular biology of the cGAS-STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS-STING axis in a number of inflammatory diseases in humans. Here, we outline the principal elements of the cGAS-STING signalling cascade and discuss the general mechanisms underlying the association of cGAS-STING activity with various autoinflammatory, autoimmune and degenerative diseases. Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Autophagy
  • Cell Death
  • Cell Proliferation
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / therapeutic use
  • Gain of Function Mutation
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / therapy*
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Models, Biological
  • Models, Molecular
  • Nucleotides, Cyclic / immunology
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / antagonists & inhibitors*
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA, Mitochondrial
  • Enzyme Inhibitors
  • Inflammation Mediators
  • Membrane Proteins
  • Nucleotides, Cyclic
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Nucleotidyltransferases