TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models

Nat Commun. 2022 Feb 3;13(1):676. doi: 10.1038/s41467-021-27948-4.


Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / prevention & control*
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / prevention & control*
  • Cells, Cultured
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Etanercept / pharmacology
  • Etanercept / therapeutic use
  • Ferroptosis / drug effects*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Glutathione / metabolism
  • Humans
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Ketones / pharmacology*
  • Ketones / therapeutic use
  • Lipid Peroxidation / drug effects
  • Mice
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use
  • Reactive Oxygen Species / metabolism
  • Synovial Membrane / cytology
  • Tumor Necrosis Factor Inhibitors / pharmacology*
  • Tumor Necrosis Factor Inhibitors / therapeutic use


  • Imidazoles
  • Ketones
  • Piperazines
  • Reactive Oxygen Species
  • Tumor Necrosis Factor Inhibitors
  • imidazole ketone erastin
  • Glutathione
  • Etanercept